Pyridinoylpiperidines as 5-HT1F agonists

ABSTRACT

The present invention relates to compounds of formula I: 
                         
or pharmaceutically acceptable acid addition salts thereof, where;
         R 1  is C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, substituted C 3 -C 7  cycloalkyl, C 3 -C 7  cycloalkyl-C 1 -C 3  alkyl, substituted C 3 -C 7  cycloalkyl-C 1 -C 3  alkyl, phenyl, substituted phenyl, heterocycle, or substituted heterocycle;   R 2  is hydrogen, C 1 -C 3  alkyl, C 3 -C 6  cycloalkyl-C 1 -C 3  alkyl, or a group of formula II       

     
       
         
         
             
             
         
       
         
         
           
             R 3  is hydrogen or C 1 -C 3  alkyl; 
             R 4  is hydrogen, halo, or C 1 -C 3  alkyl; 
             R 5  is hydrogen or C 1 -C 3  alkyl; 
             R 6  is hydrogen or C 1 -C 6  alkyl; and 
             n is an integer from 1 to 6 inclusively. 
           
         
       
    
     The compounds of the present invention are useful for activating 5-HT lF  receptors, inhibiting neuronal protein extravasation, and for the treatment or prevention of migraine in a mammal. The present invention also relates to a process for the synthesis of intermediates in the synthesis of compounds of Formula I.

RELATED APPLICATIONS

This application is a continuation and claims the benefit of priorityunder 35 U.S.C. 120 to U.S. non-provisional application Ser. No.12/221,919, filed Aug. 7, 2008, which is a continuation of U.S.non-provisional application Ser. No. 10/509,770, filed Sep. 28, 2004,now U.S. Pat. No. 7,423,050, which is a U.S. national stage application,filed under 35 U.S.C. 371, of International Application PCT/US03/08455,filed Mar. 27, 2003, which claims priority to U.S. provisionalApplication No. 60/369,088, filed Mar. 29, 2002, the disclosures of eachof which are incorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

Until recently, theories regarding the pathophysiology of migraine havebeen dominated since 1938 by the work of Graham and Wolff. Arch. Neurol.Psychiatry, 39:737-63, 1938. They proposed that the cause of migraineheadache was vasodilatation of extracranial vessels. This view wassupported by knowledge that ergot alkaloids and sumatriptan, ahydrophilic 5-HT₁ agonist which does not cross the blood-brain barrier,induce contraction of cephalic vascular smooth muscle and are effectivein the treatment of migraine. Humphrey, et al., Ann. NY Acad. Sci.,600:587-600, 1990. Recent work by Moskowitz has shown, however, that theoccurrence of migraine headaches is independent of changes in vesseldiameter. Cephalalgia, 12:5-7, 1992.

Moskowitz has proposed that currently unknown triggers for painstimulate trigeminal ganglia that innervate vasculature within thecephalic tissue, giving rise to release of vasoactive neuropeptides fromaxons on the vasculature. These released neuropeptides then activate aseries of events, a consequence of which is pain. This neurogenicinflammation is blocked by sumatriptan and ergot alkaloids by mechanismsinvolving 5-HT receptors, believed to be closely related to the5-HT_(1D) subtype, located on the trigeminovascular fibers. Neurology,43(suppl. 3):S16-S20 1993. Sumatriptan, in fact, has high affinity forthe 5-HT_(1B) and 5-HT_(1D) receptors, Ki=10.3 nM and 5.1 nM,respectively, which activity may be indicative of vasoconstrictiveactivity. Sumatriptan and similar compounds previously advanced for thetreatment of migraine had tended to be selected on the basis of thisvasoconstrictive activity under the premises of the prior art models formigraine.

Serotonin (5-HT) exhibits diverse physiological activity mediated by atleast seven receptor classes, the most heterogeneous of which appears tobe 5-HT₁. A human gene which expresses one of these 5-HT₁ receptorsubtypes, named 5-HT_(1F), was isolated by Kao and coworkers. Proc.Natl. Acad. Sci. USA, 90:408-412, 1993. This 5-HT_(1F) receptor exhibitsa pharmacological profile distinct from any serotonergic receptor yetdescribed. It was found that sumatriptan, in addition to the abovementioned strong affinities for the 5-HT_(1B) and 5-HT_(1D) receptors,also has affinity for this receptor subtype, with a K_(i) of about 23nM. This suggests a possible role of the 5-HT_(1F) receptor in migraine.

Various 5-HT_(1F) receptor agonists have subsequently been developedwhich have shown relative selectivity for the 5-HT_(1F) receptorsubclass and it has been shown that such selectivity generally reducesthe vasoconstrictive activity characteristic of other compounds advancedas potential agents for the treatment of migraine and associateddisorders.

Included among these 5-HT_(1F) receptor agonists are compounds disclosedin the following:

-   -   U.S. Pat. Nos. 5,708,187 and 5,814,653, describing a family of        6-substituted-3-amino(alkyl)-tetrahydrocarbazoles and        7-substituted-4-amino(alkyl)cyclohepta[7,6b]Indoles;    -   U.S. Pat. Nos. 5,521,196, 5,721,252, 5,521,197, and WO 96/29075,        describing various families of 5-substituted        piperidin-3-yl-indoles and 5-substituted 1,2,3,6        tetrahydropyridin-3-yl-indoles;    -   WO 97/13512 describing a family of 5-substituted        3-aminoethylindoles;    -   WO 98/46570 describing a family of 5-substituted indoles,        pyrrolo[3,2-b]pyridines, benzofurans, and benzothiophenes,        having the 3-position substituted with octahydroindolizinyl,        octahydro-2H-quinolizinyl, decahydropyrido[1,2-a]azepinyl,        1,2,3,5,8,8a-hexahydroindolizinyl,        1,3,4,6,9,9a-hexahydro-2H-quinolizinyl, or        1,4,6,7,8,9,10,10a-octahydropyrido[1,2-a]azepinyl;    -   WO 98/20875 and WO 99/25348 describing two families of        5-substituted piperidin-3-yl-azaindoles and 5-substituted        1,2,3,6-tetrahydropyridin-3-yl-azaindoles;    -   WO 00/00487 describing a family of 5-substituted (piperidin-3-yl        or 1,2,3,6-tetrahydropyridin-3-yl)indoles, azaindoles,        benzofurans, and benzothiophenes;    -   WO 98/08502 describing a family of        8-substituted-1,2,3,4-tetrahydro-2-dibenzofuranamines and        9-substituted-2-aminocyclohepta[b]benzofurans;    -   WO 98/55115 describing a family of        3-amino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxamides and        4-amino-10H-cyclohepta[7,6-b]indole-7-carboxamides;    -   WO 98/15545 describing a select family of 3,5-disubstituted        indoles and benzofurans;    -   WO 00/00490 describing a family of 5-allyl-substituted        (piperidin-3-yl or 1,2,3,6-tetrahydropyridin-3-yl)indoles,        azaindoles, benzofurans, and benzothiophenes;    -   WO 00/47559 describing a family of        4-(3-substituted-benzoyl)piperidines;    -   WO 00/50426 describing a family of 3,5-disubstituted        azabenzofurans; and    -   WO 00/34266 describing a family of 3-heteroaryl-5-[2-(aryl or        heteroaryl)-2-oxoethyl]indoles.

Continued research has now surprisingly yielded a new and unexpectedclass of novel selective 5-HT_(1F) agonists having distinct chemical andreceptor binding properties, which inhibit peptide extravasation, whileavoiding significant vasoconstrictive activity, and are therefore usefulfor the treatment of migraine and other 5-HT_(1F) receptor associateddisorders. Furthermore, the compounds of the present invention mayprovide improved solubility, which facilitates suitability in preferredformulations, such as sublingual, buccal, and/or nasal formulations.

SUMMARY OF THE INVENTION

The present invention relates to pyridinoylpiperidine compounds of thegeneral formula I:

and pharmaceutically acceptable acid addition salts thereof, where;

R¹ is C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₃-C₇ cycloalkyl,substituted C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-C₁-C₃ alkyl, substitutedC₃-C₇ cycloalkyl-C₁-C₃ alkyl, phenyl, substituted phenyl, heterocycle,or substituted heterocycle;

R² is hydrogen, C₁-C₃ alkyl, C₃-C₆ cycloalkyl-C₁-C₃ alkyl, or a group offormula II

R³ is hydrogen or C₁-C₃ alkyl;

R⁴ is hydrogen, halo, or C₁-C₃ alkyl;

R⁵ is hydrogen or C₁-C₃ alkyl;

R⁶ is hydrogen or C₁-C₆ alkyl; and

n is an integer from 1 to 6 inclusively.

In one preferred embodiment, the present invention relates topyridinoylpiperidine compounds of the general formula I:

and pharmaceutically acceptable acid addition salts thereof, wherein;

R¹ is phenyl, substituted phenyl, heterocycle or substitutedheterocycle;

R² is hydrogen or C₁-C₂ alkyl;

R³ is hydrogen or methyl; and

R⁴ and R⁵ are both hydrogen.

Other preferred compounds are those of formula I wherein R³ is hydrogen.

This invention also relates to pharmaceutical formulations comprising acompound of formula I, or a pharmaceutically acceptable acid additionsalt thereof, and a pharmaceutical carrier, diluent, or excipient. Inpreferred embodiments of this aspect of the present invention, there areprovided pharmaceutical formulations containing a compound of formula I,or a pharmaceutically acceptable salt thereof, adapted for theactivation of 5-HT_(1F) receptors, for the inhibition of neuronalprotein extravasation, for the treatment or prevention of migraine,and/or the treatment or prevention of anxiety in mammals, particularlyhumans.

In addition, the present invention relates to a method for activating5-HT_(1F) receptors in mammals, particularly humans, comprisingadministering to a mammal in need of such activation an effective amountof a compound of formula I, or a pharmaceutically acceptable acidaddition salt thereof.

Moreover, the current invention relates to a method for inhibitingneuronal protein extravasation in mammals, particularly humans,comprising administering to a mammal in need of such inhibition aneffective amount of a compound of formula I, or a pharmaceuticallyacceptable acid addition salt thereof.

Additionally, the present invention relates to a method for treating orpreventing migraine in mammals, particularly humans, comprisingadministering to a mammal in need of such treatment or prevention, aneffective amount of a compound of formula I, or a pharmaceuticallyacceptable acid addition salt thereof.

Additionally, the present invention relates to a method for treatinganxiety in mammals, particularly humans, comprising administering to amammal in need of such treatment or prevention, an effective amount of acompound of formula I, or a pharmaceutically acceptable acid additionsalt thereof.

In another aspect, the present invention relates to a compound offormula I, or a pharmaceutically acceptable acid addition salt thereof,for use in the activation of 5-HT_(1F) receptors, in the inhibition ofneuronal protein extravasation, in the treatment or prevention ofmigraine, and/or in the treatment of anxiety in mammals, particularlyhumans. That is to say, the present invention relates to the use of acompound of formula I as a medicament for the activation of 5-HT_(1F)receptors, for the inhibition of neuronal protein extravasation, for thetreatment or prevention of migraine, and/or for the treatment of anxietyin mammals, particularly humans.

Additionally, the present invention relates to the use of one or morecompounds of formula I in the manufacture of a medicament for theactivation of 5-HT_(1F) receptors, for the inhibition of neuronalprotein extravasation, for the treatment or prevention of migraine,and/or for the treatment of anxiety in mammals, particularly humans.

Furthermore, the present invention provides for methods for thetreatment of 5-HT_(1F) mediated disorders comprising administering to amammal in need of such treatment, particularly a human, an effectiveamount of a compound of formula I, or a pharmaceutically acceptable acidaddition salt thereof.

In another aspect of the present invention, there is provided a processfor the synthesis of compounds of formula I and of novel intermediatesin the synthesis. In one embodiment, the present invention provides aprocess for preparing a 2-halo-6-(piperidin-4-carbonyl)pyridine compoundof formula III

where X is bromo or chloro;

R⁸ is an amino protecting group, C₁-C₃ alkyl, C₃-C₆ cycloalkyl-C₁-C₃alkyl, or a group of formula II

R⁶ is hydrogen or C₁-C₆ alkyl; and

-   -   n is an integer from 1 to 6 inclusively;        comprising

1) reacting a 2,6-dihalopyridine selected from the group consisting of2,6-dibromopyridine and 2,6-dichloropyridine, with n-butyl lithium toform 2-halo-6-lithium-pyridine; and then

2) reacting the 2-halo-6-lithium-pyridine with a substitutedaminocarbonylpiperidine compound of formula IV

wherein R⁹ and R¹⁰ are each methyl, or R⁹ and R¹⁰, together with thenitrogen to which they are attached, combine to form azetidinyl,pyrrolidinyl, or piperidinyl.

In a particular embodiment of this aspect of the present invention,there is provided a process for preparing a2-bromo-6-(piperidin-4-carbonyl)pyridine compound of formula III

wherein R⁷ is C₁-C₃ n-alkyl, or an amino protecting group;comprising reacting 2,6-dibromopyridine with n-butyl lithium to form2-bromo-6-lithium pyridine, and then reacting the 2-bromo-6-lithiumpyridine with a 4-(N,N′-dimethylamino)carbonyl piperidine compound offormula IV

in a methyl tert-butyl ether solvent.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment of the present invention is a method for increasingactivation of 5-HT_(1F) receptors, while avoiding vasoconstrictiveactivity, for treating a variety of disorders that have been linked todecreased neurotransmission of serotonin in mammals. Included amongthese disorders are migraine, general pain, trigeminal neuralgia, dentalpain or temperomandibular joint dysfunction pain, anxiety, generalanxiety disorder, panic disorder, depression, disorders of sleep,chronic fatigue syndrome, premenstrual syndrome or late luteal phasesyndrome, post-traumatic syndrome, memory loss, dementia includingdementia of aging, social phobia, autism, attention deficithyperactivity disorder, disruptive behavior disorders, impulse controldisorders, borderline personality disorder, obsessive compulsivedisorder, premature ejaculation, erectile dysfunction, bulimia, anorexianervosa, alcoholism, tobacco abuse, mutism, and trichotillomania. Thecompounds of this invention are also useful as a prophylactic treatmentfor migraine. Any of these methods employ a compound of formula I.

In those instances where the disorders which can be treated by serotoninagonists are known by established and accepted classifications, theirclassifications can be found in various sources. For example, atpresent, the fourth edition of the Diagnostic and Statistical Manual ofMental Disorders (DSM-IV™) (1994, American Psychiatric Association,Washington, D.C.), provides a diagnostic tool for identifying many ofthe disorders described herein. Also, the International Classificationof Diseases, Tenth Revision (ICD-10), provides classifications for manyof the disorders described herein. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies, and classificationsystems for disorders described herein, including those as described inthe DSM-IV and ICD-10, and that terminology and classification systemsevolve with medical scientific progress.

The use of a compound of formula I for the activation of the 5-HT_(1F)receptor, for the inhibition of neuronal peptide extravasation, ingeneral or due to stimulation of the trigeminal ganglia specifically,and/or for the treatment of any of the disorders described above, areall embodiments of the present invention.

Likewise, the use of a compound of formula I, or a combination of morethan one compound of formula I, in the manufacture of a medicament forthe activation of the 5-HT_(1F) receptor, for the inhibition of neuronalpeptide extravasation, in general or due to stimulation of thetrigeminal ganglia specifically, and/or for the treatment of any of thedisorders described above, are also all embodiments of the presentinvention. The general chemical terms used throughout have their usualmeanings. For example, the term alkyl refers to a branched or unbranchedsaturated hydrocarbon group. The term “n-alkyl”refers to an unbranchedalkyl group. The term “C_(x)-C_(y) alkyl” refers to an alkyl grouphaving between x and y carbon atoms, inclusively, in the branched orunbranched hydrocarbon group. By way of illustration, but withoutlimitation, the term “C₁-C₄ alkyl” refers to a straight chain orbranched hydrocarbon moiety having from 1 to 4 carbon atoms, includingmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, andtert-butyl. The term “C₁-C₄ n-alkyl” refers to straight chainhydrocarbon moieties having from 1 to 4 carbon atoms including methyl,ethyl, n-propyl, and n-butyl. The term “C₃-C₆ cycloalkyl” refers tocyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “C₃-C₇cycloalkyl” also includes cycloheptyl. Cycloalkylalkyl refers tocycloalkyl moieties linked through an alkyl linker chain, as forexample, but without limitation, cyclopropylmethyl, cyclopropylethyl,cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl,cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl,cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, andcyclohexylpropyl. Each alkyl, cycloalkyl, and cycloalkylalkyl group maybe optionally substituted as specified herein.

The terms “alkoxy”, “phenyloxy”, “benzoxy” and “pyrimidinyloxy” refer toan alkyl group, phenyl group, benzyl group, or pyrimidinyl group,respectively, each optionally substituted, that is bonded through anoxygen atom.

The terms “alkylthio”, “phenylthio”, and “benzylthio” refer to an alkylgroup, phenyl group, or benzyl group, respectively, each optionallysubstituted, that is bonded through a sulfur atom.

The term “C₁-C₄ acyl” refers to a formyl group or a C₁-C₃ alkyl groupbonded through a carbonyl moiety. The term “C₁-C₄ alkoxycarbonyl” refersto a C₁-C₄ alkoxy group bonded through a carbonyl moiety.

The term “halo” refers to fluoro, chloro, bromo, or iodo. Preferred halogroups are fluoro, chloro, and bromo. More preferred halo groups arefluoro and chloro.

The term “heterocycle” is taken to mean a saturated or unsaturated 5- or6-membered ring containing from 1 to 3 heteroatoms selected fromnitrogen, oxygen and sulfur, said ring optionally being benzofused.Exemplary heterocycles, for the purposes of the present invention,include furanyl, thiophenyl (thienyl), pyrrolyl, pyrrolidinyl,pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl,imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl,pyridazinyl, and the like. Benzofused heterocyclic rings includeisoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl,benzofuranyl, benzothiophenyl, indolyl, and the like, all of which maybe optionally substituted, which also of course includes optionallysubstituted on the benzo ring when the heterocycle is benzofused.

Preferred heterocycles include pyridinyl, indolyl, furanyl,benzofuranyl, thiophenyl, benzodioxolyl, and thiazolidinyl, all of whichmay be optionally substituted.

Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio,means an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio group,respectively, substituted one or more times independently with asubstituent selected from the group consisting of halo, hydroxy, andC₁-C₃ alkoxy. By way of illustration, but without limitation, examplesinclude trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl,3-hydroxypropyloxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio,3-ethoxypropyloxy, 3-ethoxy-4-chlorocyclohexyl, and the like. Preferredsubstitutions include substitution 1-5 times with halo, eachindependently selected, or substituted 1-3 times with halo and 1-2 timesindependently with a group selected from hydroxy and C₁-C₃ alkoxy, orsubstituted 1-3 times independently with a group selected from hydroxyand C₁-C₃ alkoxy, provided that no more than one hydroxy and/or alkoxysubstituent may be attached through the same carbon.

The terms “substituted phenyl” and “substituted heterocycle” are takento mean that the cyclic moiety in either case is substituted with one ormore halo substituents, preferably one to five, each independentlyselected; or substituted with one or more substituents, preferably oneto two substituents, independently selected from the group consisting ofhalo, C₁-C₄ alkyl, C₁-C₄ alkoxy, and C₁-C₄ alkylthio, wherein eachalkyl, alkoxy and alkylthio substituent can be further substitutedindependently with C₁-C₂ alkoxy or with one to five halo groups selectedfrom fluoro and chloro; or substituted with one substituent selectedfrom the group consisting of phenyloxy, benzyloxy, phenylthio,benzylthio, and pyrimidinyloxy, wherein the phenyloxy, benzyloxy,phenylthio, benzylthio, and pyrimidinyloxy moiety can be furthersubstituted with one to two substituents selected from the groupconsisting of halo, C₁-C₂ alkyl, and C₁-C₂ alkoxy; or substituted withone substituent selected from the group consisting of C₁-C₄ acyl andC₁-C₄ alkoxycarbonyl, and further substituted with zero to onesubstituent selected from the group consisting of halo, C₁-C₄ alkyl,C₁-C₄ alkoxy, and C₁-C₄ alkylthio. When a substituent is halo, preferredhalo groups are fluoro, chloro, and bromo.

Pd₂(dba)₃ means tris(dibenzylidineacetone)-dipalladium(0).

BINAP means 2,2′-bis(diphenylphosphino)-1,1′binaphthyl.

DMF means N,N-dimethylformamide.

HATU means O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

Collidine means trimethylpyridine.

HRMS means High Resolution Mass Spectrum.

CIMS means Chemical Ionization Mass Spectrum.

APCI MS means Atmospheric Pressure Chemical Ionization Mass Spectrum.

The term “amino protecting group” as used in this specification refersto a substituents commonly employed to block or protect the aminofunctionality while reacting other functional groups on the compound.Examples of such amino-protecting groups include the formyl group, thetrityl group, the phthalimido group, the acetyl group, thetrichloroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetylgroups, urethane-type blocking groups such as benzyloxycarbonyl,9-fluorenylmethoxycarbonyl (“FMOC”), and the like; and like aminoprotecting groups. The species of amino protecting group employed is notcritical so long as the derivatized amino group is stable to theconditions of subsequent reactions on other positions of the moleculeand can be removed at the appropriate point without disrupting theremainder of the molecule. Further examples of groups referred to by theabove terms are described by T. W. Greene, “Protective Groups in OrganicSynthesis”, John Wiley and Sons, New York, N.Y., 1991, Chapter 7hereafter referred to as “Greene”.

The term “pharmaceutical” or “pharmaceutically acceptable” when usedherein as an adjective, means substantially non-toxic and substantiallynon-deleterious to the recipient.

By “pharmaceutical formulation” it is further meant that the carrier,solvent, excipients and salt must be compatible with the activeingredient of the formulation (e.g. a compound of formula I). It isunderstood by those of ordinary skill in this art that the terms“pharmaceutical formulation” and “pharmaceutical composition” aregenerally interchangeable, and they are so used for the purposes of thisapplication.

The term “acid addition salt” refers to a salt of a compound of formulaI prepared by reaction of a compound of formula I with a mineral ororganic acid. For exemplification of pharmaceutically acceptable acidaddition salts see, e.g., Berge, S. M, Bighley, L. D., and Monkhouse,D.C., J. Pharm. Sci., 66:1, 1977. Since the compounds of this inventionare amines, they are basic in nature and accordingly react with any of anumber of inorganic and organic acids to form pharmaceuticallyacceptable acid addition salts. Since some of the free amines of thecompounds of this invention are typically oils at room temperature, itis preferable to convert the free amines to their pharmaceuticallyacceptable acid addition salts for ease of handling and administration,since the latter are routinely solid at room temperature.

The pharmaceutically acceptable acid addition salts of the invention aretypically formed by reacting a compound of formula I with an equimolaror excess amount of acid. Alternatively, hemi-salts can be formed byreacting a compound of formula I with the desired acid in a 2:1 ratio,compound to acid. The reactants are generally combined in a mutualsolvent such as diethylether, tetrahydrofuran, methanol, ethanol,isopropanol, benzene, or the like. The salts normally precipitate out ofsolution within about one hour to about ten days and can be isolated byfiltration or other conventional methods.

Inorganic acids commonly employed to form such salts includehydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,phosphoric acid, and the like. Organic acids commonly employed to formsuch salts include p-toluenesulfonic acid, methanesulfonic acid, oxalicacid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citricacid, benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, hemisuccinate, suberate, sebacate, fumarate, maleate,butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycollate,tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like. Preferredpharmaceutically acceptable salts are those formed with hydrochloricacid and succinic acid.

The term “effective amount” means an amount of a compound of formula Iwhich is capable of activating 5-HT_(1F) receptors and/or inhibitingneuronal protein extravasation.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

All enantiomers, diastereomers, and mixtures thereof, are includedwithin the scope of the present invention. For example, the compounds offormula I wherein R⁵ is other than hydrogen contain two chiral centers,one at the 4-position of the piperidine ring, and one where R⁵ attachesto the piperidine ring. By way of illustration, but without limitation,the four stereoisomers ofN-[6-(1,2-dimethylpiperidine-4-carbonyl)-pyridin-2-yl]-isonicotinamideare as follows, wherein the chiral centers are indicated with asterisks,“*”, and the R and S designations are as indicated.

While all enantiomers, diastereomers, and mixtures thereof, are usefulas 5-HT_(1F) agonists, single enantiomers and single diastereomers arepreferred. Furthermore, while all of the compounds of this invention areuseful as 5-HT_(1F) agonists, certain classes are preferred. Thefollowing paragraphs describe such preferred classes.

-   -   1) R¹ is phenyl, substituted phenyl, heterocycle, or substituted        heterocycle;    -   2) R¹ is substituted phenyl;    -   3) R¹ is mono- or di-substituted phenyl wherein the substituents        are independently selected from halo, C₁-C₄ alkyl, C₁-C₄ alkoxy,        trifluoromethyl, trifluoromethoxy, trifluoroethoxy, phenyloxy,        and benzyloxy;    -   4) R¹ is mono- or di-substituted phenyl wherein the substituents        are independently selected from halo, C₁-C₂ alkoxy,        trifluoromethyl, trifluoromethoxy, and trifluoroethoxy;    -   5) R¹ is di- or tri-halo substituted phenyl;    -   6) R¹ is heterocycle or substituted heterocycle;    -   7) R¹ is a substituted or unsubstituted heterocycle selected        from the group consisting of furanyl, thiophenyl, pyrrolyl,        pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl,        pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl,        thiazolyl, thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl,        pyrazinyl, pyridazinyl, isoquinolinyl, benzoxazolyl,        benzodioxolyl, benzothiazolyl, quinolinyl, benzofuranyl,        benzothiophenyl, indolyl;    -   8) R¹ is a substituted or unsubstituted heterocycle selected        from the group consisting of pyridinyl, indolyl, benzofuranyl,        furanyl, thiophenyl, benzodioxolyl, and thiazolidinyl;    -   9) R¹ is a substituted or unsubstituted heterocycle selected        from the group consisting of pyridinyl, furanyl, thiophenyl;    -   10) R¹ is mono-, di-, or tri-halo-substituted heterocycle, each        halo group being independently selected;    -   11) R¹ is mono- or di-substituted heterocycle, wherein one of        the substituents is selected from the group consisting of C₁-C₂        alkoxy, phenoxy, and phenylthio;    -   12) R² is hydrogen or C₁-C₃ alkyl;    -   13) R² is hydrogen or methyl;    -   14) R² is C₃-C₆ cycloalkyl-C₁-C₃ alkyl;    -   15) R² is pyrazolylalkyl or N-substituted pyrazolylalkyl;    -   16) R² is pyrazol-4-yl-ethyl;    -   17) R² is 1-(C₁-C₃ alkyl)pyrazol-4-yl-ethyl;    -   18) R³ is hydrogen;    -   19) R³ is methyl;    -   20) R³ is ethyl;    -   21) R⁴ is hydrogen;    -   22) R⁴ is halo;    -   23) R⁴ is fluoro or chloro;    -   24) R⁴ is C₁-C₃ alkyl;    -   25) R⁴ is methyl;    -   26) R⁵ is hydrogen;    -   27) R⁵ is C₁-C₃ alkyl;    -   28) R⁵ is methyl;    -   29) R² is hydrogen or methyl, and R³, R⁴ and R⁵ are all        hydrogen;    -   30) R² is hydrogen or methyl, and R³ is methyl, and R⁴ and R⁵        are both hydrogen;    -   31) R¹ is mono- or di-substituted phenyl wherein the        substituents are independently selected from halo, C₁-C₂ alkoxy,        trifluoromethyl, trifluoromethoxy, and trifluoroethoxy, R² is        hydrogen or methyl, and R³, R⁴ and R⁵ are hydrogen;    -   32) R¹ is a substituted or unsubstituted heterocycle selected        from the group consisting of pyridinyl, indolyl, benzofuranyl,        furanyl, thiophenyl, benzodioxolyl, and thiazolidinyl, R² is        hydrogen or methyl, and R³, R⁴ and R⁵ are hydrogen;    -   33) R¹ is substituted phenyl, R² is hydrogen or methyl, and R³,        R⁴ and R⁵ are all hydrogen;    -   34) R¹ is substituted phenyl, R² is hydrogen or methyl, and R³        is methyl, and R⁴ and R⁵ are both hydrogen;    -   35) R¹ is mono- or di-substituted phenyl wherein the        substituents are independently selected from halo, C₁-C₂ alkoxy,        trifluoromethyl, trifluoromethoxy, and trifluoroethoxy, R² is        hydrogen or methyl, R³ is methyl and R⁴ and R⁵ are hydrogen;    -   36) R¹ is di- or tri-halo substituted phenyl, R² is hydrogen or        methyl, and R³, R⁴ and R⁵ are all hydrogen;    -   37) R¹ is di- or tri-halo substituted phenyl, R² is hydrogen or        methyl, and R³ is methyl, and R⁴ and R⁵ are both hydrogen;    -   38) R¹ is a substituted or unsubstituted heterocycle selected        from the group consisting of pyridinyl, indolyl, benzofuranyl,        furanyl, thiophenyl, benzodioxolyl, and thiazolidinyl, R² is        hydrogen or methyl, R³ is methyl, and R⁴ and R⁵ are hydrogen;    -   39) any compound exemplified;    -   40) the compound is an acid addition salt;    -   41) the compound is a hydrochloride salt;    -   42) the compound is the dihydrochloride salt.    -   43) the compound is the hemisuccinate salt;    -   44) the compound is the succinate salt; and    -   45) the compound is the disuccinate salt.

It will be understood that the above classes may be combined to formadditional preferred classes, as for example the combination ofpreferred selections for two or more substituents. Illustrative examplesof combinations of preferred classes forming additional preferredclasses are:

-   -   46) the combination of any one of preferred classes 1), 2), 8)        or 9) with preferred classes 21), and 26);    -   47) the combination of any one of preferred classes 1), 2), 8)        or 9) with preferred classes 21), and 27);    -   48) the combination of any one of preferred classes 1), 2), 8)        or 9) with preferred classes 21), and 28);    -   49) the combination of any one of preferred classes 1), 2), 8)        or 9) with preferred classes 23), and 26);    -   50) the combination of any one of preferred classes 1), 2), 8)        or 9) with preferred classes 23), and 28);    -   51) the combination of any one of preferred classes 1), 2), 8)        or 9) with preferred classes 25), and 26);    -   52) the combination of any one of preferred classes 1), 2), 8)        or 9) with preferred classes 25), and 28);    -   53) the combination of any one of the preferred combinations        46)-52) with preferred classes 12) and 18);    -   54) the combination of any one of the preferred combinations        46)-52) with preferred classes 12) and 19);    -   55) the combination of any one of the preferred combinations        46)-52) with preferred classes 13) and 18);    -   56) the combination of any one of the preferred combinations        46)-52) with preferred classes 13) and 19);    -   57) the combination of any one of the preferred combinations        46)-52) with preferred classes 14) and 18);    -   58) the combination of any one of the preferred combinations        46)-52) with preferred classes 14) and 19);    -   59) the combination of any one of the preferred combinations        46)-52) with preferred classes 15) and 18); and    -   60) the combination of any one of the preferred combinations        46)-52) with preferred classes 15) and 19).

In addition to those compounds presented in the examples, the followingcompounds further illustrate the scope of the present invention:

-   1)    4-Fluoro-N-[6(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide;-   2)    2,4-Difluoro-N-[6(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   3) N-[6(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   4)    2-Chloro-4-fluoro-N-[6(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   5)    2-Chloro-N-[6(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   6)    2,4,6-Trifluoro-N-[6-(piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   7) 1H-5-Trifluoromethyl-indole-3-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   8)    N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-trifluoromethoxy-benzamide-   9) 3-Bromo-thiophene-2-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   10)    4-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-trifluoromethyl-benzamide-   11)    2,4,6-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   12)    2-Chloro-6-fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   13)    2,4,6-Trifluoro-N-methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   14)    2,4,6-Trifluoro-N-methyl-N-[6-(piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   15)    2,4,6-Trifluoro-N-methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   16)    2,4,6-Trifluoro-N-ethyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   17)    2-Chloro-4-fluoro-N-[6-(piperidin-4-carbonyl)-pyridin-2-yl]-benzamide-   18)    2-Chloro-4-fluoro-N-methyl-N-[6-(1-methyl-piperidin-4-carbonyl)-pyridin-2-yl]-benzamide-   19) 1H-5-Fluoro-indole-3-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   20) Cyclopropanecarboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   21)    3-Methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-butanamide-   22) Thiophene-2-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   23) Furan-2-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   24)    2-Chloro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   25) Furan-3-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   26)    3,4-Difluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   27)    N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-isonicotinamide-   28)    2-Methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   29)    2-Bromo-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   30) Thiophene-3-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   31)    2-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-isonicotinamide-   32)    4-Chloro-2-methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   33)    2-Ethoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   34)    N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-phenoxy-benzamide-   35)    5-Chloro-2-methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   36)    2-Methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-4-methylsulfanyl-benzamide-   37) 2,3-Dihydro-benzofuran-7-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   38)    2-Benzyloxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   39)    N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-propoxy-benzamide-   40) 2,2-Difluoro-benzo[1,3]dioxole-4-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   41)    4-Methoxy-2-(2-methoxy-ethoxy)-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   42)    5-Bromo-2-methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   43)    2-(4,6-Dimethoxy-pyrimidin-2-yloxy)-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   44) N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-butanamide-   45) Cyclohexanecarboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   46)    N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-3-phenyl-propionamide-   47)    2,6-Difluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   48)    2-Ethoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-nicotinamide-   49)    N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-phenoxy-nicotinamide-   50) 3-Acetyl-thiazolidine-4-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   51)    N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-phenylsulfanyl-nicotinamide-   52)    5-Methoxy-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-(2,2,2-trifluoro-ethoxy)-benzamide-   53)    2-Methoxy-6-methyl-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   54)    N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-terephthalamic    acid methyl ester-   55) Cyclobutanecarboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   56)    2-(2-Chloro-1,1,2-trifluoro-ethoxy)-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   57)    2-Chloro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   58)    2,5-Difluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   59)    3,4-Difluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   60)    4-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-trifluoromethyl-benzamide-   61)    2-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-6-trifluoromethyl-benzamide-   62)    2,3,4-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   63)    2,4,5-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   64) 3-Chloro-thiophene-2-carboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   65)    2,6-Dichloro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide-   66)    2-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-4-trifluoromethyl-benzamide-   67) Cyclopentanecarboxylic acid    [6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-amide-   69) N-[6-(1-Methyl-piperidine-4-carbonyl)-pyridin-2-yl]-nicotinamide

It is preferred that the mammal to be treated by the administration ofcompounds of this invention is human.

The compounds of the present invention may be synthesized through acondensation of a 6-lithio anion of 2-chloropyridine with 1-substituted-or N-protected piperidine-4-carboxylic acid methoxy-methylamide,followed by conversion of the 2-halo group to an amino group, andsubsequent condensation with the appropriate R¹-acylhalide compound.(see Scheme 1.)

Suitable reaction conditions for the steps of this scheme are well knownin the art and appropriate substitutions of solvents and reagents arewithin the skill of the art. See for example, J. C. S. Perkin T. (24),3597-3600 (1997) for the initial condensation.

Typically 2-chloropyridine is activated by reaction with a mixture ofn-butyl lithium and 2-dimethylamino-ethanol in a suitable solvent, suchas hexane, at −78° C. The reaction is generally complete within about anhour. Next 1-R⁷-substituted-piperidine-4-carboxylic acidmethoxy-methyl-amide in an organic solvent, such as hexane is added andstirred to form the 2-chloropyridinoyl-piperidine intermediate. Thereaction is generally complete within about an hour. When the desiredfinal R² substituent is hydrogen, the piperidinyl nitrogen should firstbe protected with an amino protecting group, the addition and laterremoval of which are accomplished by standard procedures well known inthe art.

Typically the first condensation reaction is quenched by the addition ofwater and the mixture is extracted multiple times with a suitablesolvent, such as ethyl acetate. This 2-chloropyridinoyl-piperidineintermediate can then be dried, as for example with anhydrous sodiumsulfate, evaporated, and then partially purified, as for example, bychromatography on a silica gel column.

Next, the 2-chloropyridinoyl-piperidine intermediate is reacted withbenzophenone imine in the presence oftris(dibenzylidineacetone)-dipalladium(0) Pd₂(dba)₃) as a catalyst, and2,2′-bis(diphenylphosphino)-1,1′binaphthyl (BINAP) and sodium t-butoxidein a suitable solvent, such as toluene, at reflux, to substitute thehalo group with the benzophenone imino group. After work-up, thisintermediate is typically reacted with hydrochloric acid in a suitablesolvent, such as tetrahydrofuran, and then purified to give thecorresponding 2-aminopyridinoyl-piperidine intermediate.

In the final stage of scheme I, the R¹ moiety is added by amide bondformation by reacting the 2-aminopyridinoyl-piperidine intermediate withthe desired R¹-acylhalide. Typically, a mixture of the2-aminopyridinoyl-piperidine intermediate, the desired R¹-acylhalide, aproton scavenger, such as triethylamine, diisopropylethylamine, and thelike, in an appropriate solvent, such as dichloromethane, THF, MTBE andthe like, is stirred at about room temperature until the reaction iscomplete, as for example, about 4 hrs. A strong base, such as sodiumhydroxide, may then be added to neutralize the reaction mixture, and thefinal product purified by normal work-up procedures.

If the piperidinyl nitrogen is protected by an amino protecting group,this group is removed after the condensation reaction with theacylhalide. The piperidinyl nitrogen can then remain as a secondaryamine for compounds of the present invention wherein R² is hydrogen, orit may be further alkylated by known procedures for compounds of thepresent invention wherein R² is C₁-C₃ alkyl, C₃-C₆ cycloalkyl-C₁-C₃alkyl, or a group of formula II

Although alternative alkylation methods are well known in the art, onetypical alkylation reaction proceeds by reductive alkylation of thesecondary amine with an appropriate aldehyde, an organic acid such asglacial acetic acid or trifluoroacetic acid, and a reducing agent suchas sodium cyanoborohydride or sodium triacetoxyborohydride, in anappropriate solvent, such as methanol or dichloromethane, wherein theappropriate aldehyde is one that will react to provide the desired R²substituent. (Michael B. Smith and Jerry March, March's Advanced OrganicChemistry: Reactions, mechanisms and Structure, 5^(th) ed., pgs1185-1187 (sec. 16-12), John Wiley & Sons, Inc., New York, 2001.) By wayof illustration, for the synthesis of compounds having R²=methyl, thedesired aldehyde would be formaldehyde, whereas for the synthesis ofcompounds having R²=3-cyclopentylpropyl, the desired aldehyde would be3-cyclopentylpropanal.

Compounds of the present invention wherein R³ is methyl or ethyl can besynthesized by Scheme 2.

The R³-aminocarbonyl-R¹ reagents are easily prepared by reacting thecorresponding R¹ acylhalide with the desired amine (methylamine,ethylamine, propylamine, or isopropylamine, as for example a 2 Msolution thereof) in an appropriate solvent, as for example methanol.Such a procedure is trivial and well known in the art.

The 2-bromopyridinoyl-piperidine intermediate is synthesized by firstreacting 2,6-dibromopyridine in a suitable organic solvent, such asdichloromethane, preferably under a nitrogen atmosphere, with 1.1equivalent of n-butyllithium in a suitable solvent, such as hexanes,preferably at low temperatures, such as −78° C. An appropriate1-R⁷-substituted-N-methoxy-N-methyl-piperidine-4-carboxamide is thenadded to the reaction mixture. The reaction is subsequently quenchedwith base, as for example, aqueous NaOH. The resulting intermediate maythen be purified by standard workup techniques, such as extraction,solvent removal and subsequent chromatography.

The 2-bromopyridinoyl-piperidine intermediate is reacted under N₂ in amixture with the desired methylaminocarbonyl-R¹, ethylaminocarbonyl-R¹,or propylaminocarbonyl-R¹, respectively,tris(dibenzylidineacetone)-dipalladium(0) (Pd₂(dba)₃),2,2′-bis(diphenylphosphino)-1,1′binaphthyl (BINAP), and sodiumt-butoxide, in a suitable solvent, such as suitably anhydrous toluene.The reaction is typically heated for several hours, as for example atabout 85° C. for 16 hours. Additional C₁-C₂ alkylaminocarbonyl-R¹,tris(dibenzylidineacetone)-dipalladium(0) (Pd₂(dba)₃),2,2′-bis(diphenylphosphino)-1,1′binaphthyl (BINAP), and sodiumt-butoxide can be added and the reaction continued for a similar periodof time to improve the reaction yield. The final product is thenpurified by common methods.

Compounds of the present invention wherein R⁴ or R⁵ are other thanhydrogen can be synthesized by the above schemes utilizing thecorresponding substituted 2-halopyridine and substituted piperidinylstarting reagents.

In a preferred embodiment, a novel condensation reaction is used tosynthesize the 2-bromopyridinoyl-piperidine intermediate to providehighly selective mono-addition, as well as higher yields of the desiredintermediate product with fewer impurities. In another preferredembodiment, a more favorable reaction is used to convert the2-bromopyridinoyl-piperidine intermediate to the2-aminopyridinoyl-piperidine intermediate in preparation for the finalcondensation reaction. (See Scheme 3.)

The novel N,N-dimethylaminocarbonylpiperidine intermediate is made inhigh yield from an R⁷-isonipicotic acid derivative by reacting the acidwith oxalyl chloride in the presence of a catalytic amount ofdimethylformamide (DMF) in a suitable solvent, such as dichloromethane,tetrahydrofuran, dichloroethane, diethylether, or the like, andconcentrating to yield an isonipecotyl chloride derivative. This is thenresuspended in a suitable solvent, such as tetrahydrofuran,dichloromethane, dichloroethane, diethylether, or the like, and reactedwith dimethylamine in the presence of a proton scavenger, as forexample, a non-nucleophilic organic base, such as triethylamine,diisopropylethylamine, or the like, and then purified to give theN,N-dimethylaminocarbonylpiperidine intermediate.

The N,N-dimethylcarbonylpiperidine intermediates of the presentinvention have the distinct advantages over the N-protectedpiperidine-4-carboxylic acid methoxy-methylamide reagents (Weinrebreagents) of the prior art, in that they are non-hygroscopic andsurprisingly provide significantly improved chemoselectivity and yieldin the subsequent condensation reaction as compared to the condensationreaction using the corresponding Weinreb reagent. This is particularlythe case when, as in a preferred embodiment, toluene ormethyl-tert-butylether (MTBE) is used as the solvent. In a yet morepreferred embodiment, MTBE is used as the solvent.

Next, 2,6-dibromopyridine is activated by reaction with n-butyllithiumin cold MTBE or toluene, preferably MTBE, to produce abromolithiumpyridine intermediate. Subsequently, theN,N-dimethylaminocarbonylpiperidine intermediate is added and themixture stirred, as for example for about an hour at between about −100°C. to about −60° C., preferably about −75° C. In a preferred embodiment,the coupling reaction is run with a ratio of the 2,6-dibromopyridine tothe N,N-dimethylaminocarbonylpiperidine intermediate of about a 1.0 toabout 2.0, more preferably with a ratio of between about 1.3 to about1.7, most preferably with a ratio of about 1.5. The reaction is thenquenched with saturated ammonium chloride at about −20° C. to about 10°C., and then neutralized with hydrochloric acid and additional water.The product can then be isolated by typical work-up procedures, as forexample, but without limitation, by extraction of the aqueous phase withdichloromethane, washing the organic fractions with acidified water (asfor example, pH 2), neutralizing the aqueous extract with sodiumhydroxide, followed by extraction with ethyl acetate, drying the organicphase, as for example with magnesium sulfate, and concentrating, as forexample, by evaporation, rotoevaporation, etc.

In another preferred embodiment, the 4-(N,N′-dimethylamino)carbonylpiperidine compound in Scheme 3 is replaced with a substitutedaminocarbonylpiperidine compound of formula IV

where R⁸, R⁹, and R¹⁰ are as defined above. Preferred compounds offormula IV are those wherein R⁹ and R¹⁰ are each methyl, or wherein R⁹and R¹⁰, together with the nitrogen to which they are attached, combineto form pyrrolidinyl. Particularly preferred are those compounds whereinR⁹ and R¹⁰, together with the nitrogen to which they are attached,combine to form pyrrolidinyl.

Compounds where R⁹ and R¹⁰, together with the nitrogen to which they areattached, combine to form azetidinyl, pyrrolidinyl, or piperidinyl, canbe synthesized by the same methods as their N,N′-dimethyl analogs, bysubstituting azetidine, pyrrolidine, or piperidine, respectively, forthe dimethylamine reagent described above.

The 4-(pyrrolidinylcarbonyl)piperidine reagents have the added advantageover the 4-(N,N′-dimethylamino)carbonyl piperidine reagents in that theytend to be even less hygroscopic and tend to produce more stablecrystals, improving the handling characteristics of the reagents. Aswith the 4-(N,N′-dimethylamino)carbonyl piperidine reagents, the4-(pyrrolidinylcarbonyl)piperidine reagents provide unexpectedsignificantly improved chemoselectivity and yield in the subsequentcondensation reaction over reactions run using the corresponding Weinrebreagents.

By way of illustration, but without limitation,1-methyl-4-(N,N′-dimethylamino)carbonyl piperidine is a low meltingpoint solid that crystallizes easily and has relatively lowhygroscopicity, particularly as compared to the corresponding Weinrebreagent. However, when the crystalline form does absorb water, itconverts to an oil. In comparison,1-methyl-4-(pyrrolidinylcarbonyl)piperidine is also a low melting pointsolid that crystallizes easily, but is even less hygroscopic than1-methyl-4-(N,N′-dimethylamino)carbonyl piperidine and produces morestable crystals, such that they retain their crystalline form even ifsome water is absorbed. 1-methyl-4-(piperidin-1-yl)carbonylpiperidinegenerally remains an oil.

In another embodiment of the present inventive process,2,6-dichloropyridine can be used instead of 2,6-dibromopyridine inscheme 3, above under similar reaction conditions, to provide thecorresponding 2-chloropyridinoylpiperidine intermediate.

In yet another preferred embodiment of the novel synthetic process, MTBEor toluene is used as the solvent, resulting in further improvedchemoselectivity in the condensation reaction. MTBE as solvent is mostpreferred.

In a further embodiment of the present inventive process, the next stepof the synthesis provides for the exchange of the halo group for anamino group by reaction of a 2-bromo-6-(piperidinylcarbonyl)pyridineintermediate, as described above, with ammonia and ethylene glycol, inthe presence of copper(I) oxide as a catalyst. In a preferredembodiment, this reaction is run in an autoclave, with typicalconditions being about 80° C. to about 110° C., preferably about 100°C., and from about 45 to about 60 psi (about 310 to about 414 kPa),typically about 50 psi (about 345 kPa). Ammonia is then removed from theorganic fraction by evacuation. Aqueous sodium hydroxide is then addedand the mixture extracted with a suitable organic solvent, as forexample, methyl-tert-butylether or dichloromethane, and then dried, asfor example, with magnesium sulfate.

In a preferred embodiment, the crude2-amino-6-(1-R⁷-piperidine-4-ylcarbonyl)pyridine intermediate is furtherpurified by crystallization of the hydrochloric salt and thenneutralizing the salt with sodium hydroxide, organic solvent extractionand solvent removal.

The final condensation reaction is as described in Scheme 1.

The following Preparations and Examples are illustrative and should notbe interpreted in any way so as to limit the scope of the invention.

Preparations

1. 2-Chloro-6-(1-methylpiperidin-4-ylcarbonyl)pyridine

Add 2-chloropyridine (1 g, 8.8 mmole) to a mixture of n-butyl lithium(1.6 M in hexane) (22 mL, 35.2 mmole) and 2-dimethylamino-ethanol (1.56g, 17.6 mmole) in hexane (20 mL at −78° C.) and stirred for 1 hour. Thenadd 1-methyl-piperidine-4-carboxylic acid methoxy-methyl-amide (3.2 g,17.6 mmole) in hexane (5 mL) and stir the mixture for 1 hour. Quench thereaction mixture with water and extract twice with ethyl acetate, drythe organic layer with anhydrous sodium sulfate, evaporate the solventand purify the residual product by chromatography on a silica gel columnto give about 1 g of the title product.

2. 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine

Heat a mixture of 2-chloro-6-(1-methylpiperidin-4-ylcarbonyl)pyridine(800 mg, 3.35 mmole), benzophenone imine (729 mg, 4.02 mmole),tris(dibenzylidineacetone)-dipalladium(0) (61 mg, 0.067 mmole),racemic-2,2′-bis(diphenylphosphino)-1,1′binaphthyl (83 mmole, 0.134mmole) and sodium t-butoxide (451 mg, 4.69 mmole) in toluene (100 mL) atreflux for 2 hours. Evaporate the solvent and re-dissolve the residue inethyl acetate, wash with water, dry with anhydrous sodium sulfate,evaporate and purify by chromatography on a silica gel column to giveabout 1 g of a benzophenone-imine intermediate. Add 1N HCl (12 mL) intoa solution of the product in THF (50 mL), and stir at room temperaturefor 2 hours. Then add 25 mL of 1N HCl and extract the mixture twice with(2:1) hexane:ethyl acetate. Basify the aqueous phase, extract withdichloromethane, dry with anhydrous sodium sulfate, evaporate thesolvent and purify the residual by chromatography on a silica gel column(ethyl acetate:2M NH₃ in methanol, 90:10) to give about 600 mg of thetitle product.

EXAMPLES 1.4-Fluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidedihydrochloride

Stir a mixture of 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine(0.150 g), 4-fluorobenzoyl chloride (0.218 g), triethylamine (0.192 mL)and dichloromethane at room temperature for 4 hours. Add 1N aqueous NaOHto basify the reaction mixture. Extract the mixture withdichloromethane, dry the organic phase with anhydrous sodium sulfate,evaporate the solvent, and purify the residue by HPLC to provide thefree base of the title compound. Re-dissolve the free base in diethylether and add excess 1 M HCl. Evaporate the solvent and dry the residueunder vacuum to obtain 80 mg of the title compound. M.p. 75-80° C.;HRMS: 342.1605 (obs.) (Cal. 342.1618).

2.2,4-Difluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidedihydrochloride

Use a method similar to the above example 1, with 2,4-difluorobenzoylchloride to obtain the title compound. M.p. 108-110° C.; mass spectrum(electric spray) m/z=360.

3.2-Chloro-4-fluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide

Use a method similar to the above example 1, with2-chloro-4-fluorobenzoyl chloride to obtain the title compound. Freebase m.p. 53-55° C.; HRMS: 376.1233 (obs.) (Cal. 376.1228). Di-HCl saltm.p. 243-245° C.; HRMS: 376.1238 (obs.) (Cal. 376.1228).

4.2-Chloro-6-fluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidemono-hydrochloride salt

Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.18 g, 0.85mmol), 2-chloro-6-fluoro-benzoyl chloride (0.318 g, 1.65 mmol), and1,4-dioxane (10 mL). Stir and heat the mixture at reflux. After 2 hr.,cool the reaction mixture to ambient temperature and concentrate. Loadthe mixture onto an SCX column (10 g), wash with methanol, and elutewith 2M ammonia/methanol. Concentrate the eluent to obtain the free baseof the title compound (0.30 g, 94%) as an oil. Dissolve the oil inmethanol (5 mL) and treat with ammonium chloride (0.045 g, 0.85 mmol).Concentrate the mixture and dry under vacuum to obtain the titlecompound. HRMS Obs. m/z 376.1237; Calc. m/z 376.1228; m.p. 155° C.(dec).

5.2-Bromo-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridine-2-yl]benzamidehydrochloride salt

Use a method similar to example 1, with 2-bromobenzoyl chloride toobtain the free base of the title compound. Dissolve the clean material(104.8 mg) in methanol and add 1 equivalent (13.9 mg) of NH₄Cl. Sonicatethe reaction mixture at room temperature for 15 min. and thenconcentrate and dry the mixture to provide the title compound as a whitesolid. Mass spectrum (ion spray): m/z=402.1 (M+1); ¹H NMR δ (d6-DMSO,ppm) 11.15 (1H, s), 8.37 (1H, bs), 8.07 (1H, t, J=7.69, 8.05, 15.74 Hz),7.74 (2H, m), 7.58 (3H, m), 3.70 (1H, bs), 2.87 (2H, m), 2.65 (3H, s),2.12 (3H, m), 1.82 (3H, m)

6.2-Chloro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide

Mix 2-Amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.223 g) and2-chlorobenzoyl chloride (0.175 g) in 1,4-dioxane (10 mL) and heat atreflux for 1 hour. Dilute with methanol (10 mL) and load on a SCX column(10 g). Wash the column with methanol, elute the product with 2 M NH₃ inmethanol, evaporate and purify the product on a silica gel column(CH₂Cl₂ with 2 M NH₃ in methanol) to obtain 0.305 g (84%) of the titlecompound: mass spectrum (electric spray) m/z=358 (M+1) and 360 (M+2+1);¹H NMR (CDCl₃): 8.60 (br s, 1H), 8.54 (d, 1H), 7.90 (dd, 1H), 7.81 (d,1H), 7.76 (dd, 1H), 7.45 (m, 3H), 3.63 (m, 1H), 2.90 (m, 2H), 2.29 (s,3H), 2.07 (m 2H), 1.85 (m, 4H).

Dissolve the free base in dichloromethane and add 1N HCl in ether (0.85mL), evaporate, and dry under vacuum to obtain the monohydrochloridesalt (0.354 g).

7. N-[6-(1-Methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidehydrochloride

Use a method similar to the above example 1, with benzoyl chloride toobtain the free base of the title compound. Re-dissolve the free base indiethyl ether and add 1 M HCl in a 1:1 molar ratio. Evaporate thesolvent and dry the residue under vacuum to obtain the title compound.HRMS: 324.1697 (obs.) (Cal. 324.1712).

8.2,4,6-Trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidemono-hydrochloride salt

Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.20 g, 0.92mmol), 2,4,6-Trifluorobenzoyl chloride (0.357 g, 1.84 mmol), and1,4-Dioxane (10 mL), and stir while heating at reflux. After 3 hr., coolthe reaction mixture to ambient temperature and concentrate. Load theconcentrated mixture onto an SCX column (10 g), wash with methanol, andelute with 2M ammonia in methanol. Concentrate the eluent to obtain thefree base of the title compound as an oil (0.365 g (>100%)). Dissolvethe oil in methanol (5 mL) and treat with ammonium chloride (0.05 g,0.92 mmol). Concentrate the mixture and dry under vacuum to obtain thetitle compound. HRMS Obs. m/z 378.1435, Calc. m/z 378.1429; m.p. 255° C.(dec).

9.2-Trifluoromethyl-4-fluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidemono-hydrochloride salt

Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.19 g, 0.87mmol), 2-trifluoromethyl-4-fluoro-benzoyl chloride (0.395 g, 1.74 mmol),and 1,4-Dioxane (50 mL). Stir and heat the mixture at reflux. After 3hr., cool the reaction mixture to ambient temperature and concentrate.Load the mixture onto an SCX column (10 g), wash with methanol, andelute with 2M ammonia/methanol. Concentrate the eluent to obtain thefree base of the title compound as an oil (0.241 g, 68%). Dissolve theoil in methanol (5 mL) and treat with ammonium chloride (0.031 g, 0.59mmol). Concentrate and dry under vacuum to obtain the title compound.HRMS Obs. m/z 410.1490, Calc. 410.1491; m.p. 145-150° C.

10.2-Trifluoromethoxy-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidemono-hydrochloride salt

Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.18 g, 0.84mmol), 2-trifluoromethoxybenzoyl chloride (0.23 g, 1.0 mmol) and1,4-Dioxane (5 mL). Stir and heat the mixture at reflux. After 3 hr.,cool the reaction mixture to ambient temperature. Load on an SCX column(10 g), wash with methanol, and elute with 2M ammonia/methanol.Concentrate the eluent to obtain the free base of the title compound(0.26 g, 76%). Dissolve the free base in methanol (10 mL) and treat withammonium chloride (0.032 g). Concentrate and dry under vacuum to obtainthe title compound. HRMS Obs. m/z 408.1517, Calc. m/z 408.1535; m.p.155-160° C.

11.3-Bromo-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-thiophene-2-carboxamidemono-hydrochloride salt

Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.104 g,0.48 mmol), 3-Bromo-thiophene-2-carbonyl chloride (0.215 g, 0.95 mmol),and 1,4-Dioxane (10 mL). Stir and heat the mixture at reflux. After 2hr., cool the reaction mixture to ambient temperature and concentrate.Load the mixture onto an SCX column (10 g), wash with methanol, andelute with 2M ammonia/methanol. Concentrate the eluent to obtain thefree base of the title compound as an oil (0.152 g, 78%). Dissolve theoil in dichloromethane (10 mL), treat with 1M hydrogen chloride inether, concentrate and dry under vacuum to obtain the title compound.HRMS Obs. m/z 408.0384, Calc. m/z 408.0381; m.p. 195-200° C.

12.1-H-indol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamidedihydrochloride salt

(i) Intermediate:1-Benzylindol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamide

Add oxalyl chloride (0.18 mL, 2.1 mmol) dropwise to a solution of1-benzylindol-3-carboxylic acid (0.48 g, 1.9 mmol) in pyridine and CH₃CN(5 mL each) cooled in an ice bath. Stir the reaction mixture for 2.25hr. and then add a suspension of2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.56 g, 1.9 mmol) inCH₃CN (5 mL) and pyridine (12 mL). Warm the reaction mixture to roomtemperature overnight. Quench the reaction with cold H₂O (20 mL) anddilute with CHCl₃. Adjust the pH to 11 with Na₂CO₃ and separate thelayers. Extract the aqueous layer with CHCl₃ (2×30 mL). Combine theorganic fractions and dry with anhydrous MgSO₄, filter and concentratethe mixture in vacuo. Purify the product by chromatography on a silicagel column, eluting with methanol/CH₂Cl₂ (5:95) followed bymethanol/CH₂Cl₂ (10:90) to afford the sub-title compound (0.44 g, 51%).¹H NMR (CD₃OD)

8.45 (d, J=8 Hz, 1H), 8.32 (s, 1H), 8.26 (m, 1H), 7.95 (t, J=8 Hz, 1H),7.72 (d, J=8 Hz, 1H), 7.45 (m, 1H), 7.22-7.37 (m, 7H), 5.51 (s, 2H),3.90 (m, 1H), 2.93-3.01 (m, 2H), 2.33 (s, 3H), 2.21-2.31 (m, 2H),1.92-1.99 (m, 2H), 1.71-1.84 (m, 2H); CIMS (Methane) m/z 453[C₂₈H₂₈N₄O₂+H]⁺.

(ii)1H-indol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamide

Add aluminum trichloride (106 mg, 0.795 mmol) to a suspension of1-benzylindol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamide(180 mg, 0.398 mmol) in benzene (6 mL) and heat the mixture at refluxfor 1.25 hr. Then add another 2 equivalents of aluminum trichloride (108mg) and continue heating at reflux for an additional 5.5 hr. Cool thereaction mixture to room temperature. Then pour the reaction into icecold H₂O (50 mL) and then dilute with ethyl acetate. Adjusted the pH ofthe solution to 11 with saturated Na₂CO₃, separate the layers andextract the aqueous layer with ethyl acetate (3×50 mL). Combined theorganic fractions, dry with Na₂SO₄, filter and concentrate in vacuo.Purify the intermediate by flash chromatography on a silica gel column,eluting with CHCl₃/methanol/NH₄OH (93:7:1) to obtain the sub-titlecompound (96 mg, 67%). ¹H NMR (CD₃OD)

8.45 (d, J=8 Hz, 1H), 8.25 (s, 1H), 8.21 (m, 1H), 7.96 (t, J=8 Hz, 1H),7.72 (d, J=8 Hz, 1H), 7.48 (m, 1H), 7.18-7.27 (m, 2H), 3.90 (m, 1H),2.94-3.01 (m, 2H), 2.31 (s, 3H), 2.19-2.28 (m, 2H), 1.92-2.02 (m, 2H),1.71-1.84 (m, 2H). CIMS (Methane) m/z 363 [C₂₁H₂₂N₄O₂]⁺.

(iii)1-H-indol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamidedihydrochloride salt

Add 2.0M HCl in diethylether (0.46 mL, 0.93 mmol) to a suspension of1H-indol-3-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamide(free base) (0.16 g, 0.44 mmol) in diethylether (10 mL). After 2 hr.filter the reaction mixture and wash the solid with diethylether toafford the title compound as a yellow solid. R_(f) 0.29 (93:7:1CHCl₃/methanol/NH₄OH); m.p. 200-218° C.; ¹H NMR (CD₃OD, complex mixtureof rotamers)

8.38 and 8.49 (s, 1H), 8.46 (m, 1H), 8.08-8.10 and 8.18-8.29 (m, 2H),7.61 and 7.72 (d, J=8 Hz, 1H), 7.52 (m, 1H), 7.26-7.32 (m, 2H), 4.01 (m,1H), 3.19-3.68 (m, 3H), 2.97 (m, 1H), 2.82 and 2.94 (s, 3H), 2.28-2.32(m, 2H), 1.68-2.02 (m, 2H); CIMS (Methane) m/z 363 [C₂₁H₂₂N₄O₂+H]⁺; HPLC(Method A) 96.7%, t_(R) 16.4 min.; anal. calculated forC₂₁H₂₂N₄O₂.2.1HCl.1.5H₂O: C, 54.12; H, 5.86; N, 12.02; Cl, 15.98. Found:C, 54.13; H, 6.03; N, 12.37; Cl, 15.71.

13.Cyclopropyl-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamidedihydrochloride salt

Add cyclopropylcarbonyl chloride (0.08 mL, 0.83 mmol) dropwise to asolution of 2-amino(6-pyridyl)-1-methyl(4-piperidyl)-ketone (221 mg,0.76 mmol) and triethylamine (0.32 mL, 2.3 mmol) in CH₂Cl₂ (5 mL) cooledin an ice bath. Warm the reaction mixture to room temperature and stirfor 3 hr. Extract the reaction mixture with CH₂Cl₂ and H₂O and adjustthe pH of the aqueous layer to 11 with Na₂CO₃. Separate the layers andextract the aqueous layer with CH₂Cl₂ (2×50 mL). Combine the organicfractions, dry (Na₂SO₄), filter and concentrate in vacuo. Purify theconcentrate by chromatography on a silica gel column, eluting with agradient of CH₂Cl₂/methanol (95:5 to 90:10) to obtain the free base ofthe title compound (180 mg, 83%). ¹H NMR (CDCl₃, complex mixture ofrotamers.)

8.81 (bs, 1H), 8.39 (d, J=8 Hz, 1H), 7.82 (t, J=8 Hz, 1H), 7.71 (d, J=8Hz, 1H), 3.50 (m, 1H), 3.13-3.21 (m, 2H), 2.51 (s, 3H), 2.37-2.48 (m,4H), 1.95-2.04 (m, 2H), 1.55 and 1.82 (m, 1H), 0.75-0.81, 0.90-0.99 and1.10-1.14 (m, 4H); APCI MS m/z 288 [C₁₆H₂₁N₃O₂+H]⁺.

Add 2.0M HCl in diethyl ether (0.95 mL, 1.9 mmol) to a solution of thefree base (180 mg, 0.626 mmol) in diethyl ether (10 mL) and methanol (3mL). After 2 hr. the reaction was filtered to afford the title compoundas a light yellow solid. R_(f) 0.47 (93:7:1 CHCl₃/methanol/NH₄OH); m.p.140-148° C.; ¹H NMR (CD₃OD, complex mixture of rotamers)

8.24 and 8.50 (m, 1H), 8.05-8.08 (m, 1H), 7.52 and 7.64 (d, J=8.0 Hz,1H), 3.98 and 4.16 (m, 1H), 3.62-3.66 (m, 1H), 3.20-3.28 and 3.44-3.56(m, 2H), 2.91-3.04 (m, 1H), 2.80 and 2.93 (s, 3H), 2.13-2.29 (m, 2H),1.57-1.79 and 1.92-2.06 (m, 3H), 1.01-1.21 (m, 4H); CIMS (Methane) m/z288 [C₁₆H₂₁N₃O₂+H]⁺; HPLC>99%, t_(R) 14.9 min.; anal. calculated forC₁₆H₂₁N₃O₂.2.3HCl.2.3H₂O: C, 46.57; H, 6.81; N, 10.18; Cl, 19.76. Found:C, 46.43; H, 6.55; N, 10.00; Cl, 19.62.

14.2-Methylprop-1-yl-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-carboxamidedihydrochloride salt

(i) Free Base:

Add 3-methylbutanoyl chloride (0.11 mL, 0.90 mmol) dropwise to asolution of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (132 mg,0.45 mmol) and triethylamine (0.19 mL, 1.4 mmol) in CH₂Cl₂ (5 mL) cooledin an ice bath. Warm the reaction mixture to room temperature and stirfor 3 hr. Dilute the reaction with CH₂Cl₂ and wash with saturated NaHCO₃(50 mL). Extract the aqueous layer with CH₂Cl₂ (2×25 mL). Combine theorganic fractions, dry (Na₂SO₄), filter and concentrate in vacuo. Purifythe product by chromatography on a silica gel column, eluting withCH₂Cl₂/methanol (95:5) to obtain the free base of the title compound (88mg, 64%). ¹H NMR (CDCl₃) δ 8.44 (d, J=8.0 Hz, 1H), 7.81-7.86 (m, 1H),7.73 (d, J=7.1 Hz, 1H), 3.50 (m, 1H), 3.00-3.18 (m, 2H), 2.18-2.46 (m,7H), 1.92-2.01 (m, 2H), 1.52-1.71 (m, 3H), 1.05 (d, J=6.6 Hz, 6H); CIMS(Methane) m/z 304 [C₁₇H₂₅N₃O₂+H]⁺.

(ii) Dihydrochloride Salt:

Add 2.0M HCl in diethyl ether (0.36 mL, 0.73 mmol) to a solution of thefree base (88 mg, 0.29 mmol) in diethyl ether (5 mL) and methanol (2mL). After 2 hr., concentrate the reaction mixture in vacuo to obtainthe title compound as a brown solid. R_(f) 0.58 (93:7:1CHCl₃/methanol/NH₄OH); m.p. 93-95° C.; ¹H NMR (CD₃OD, complex mixture ofrotamers)

8.35 (m, 1H), 7.95 (m, 1H), 7.77 (m, 1H), 4.06 and 4.25 (m, 1H),3.43-3.52 and 3.61-3.65 (m, 2H), 3.18-3.28 (m, 2H), 2.81-2.94 (m, 3H),2.21-2.37 (m, 5H), 1.90-2.02 (m, 2H), 1.03-1.05 (m, 6H); CIMS (Methane)m/z 304 [C₁₇H₂₅N₃O₂+H]⁺; HPLC 98.4%, Symmetry® series C18 column, WatersCorporation, Milford, Mass. (4.6×250 mm); anal. calculated forC₁₇H₂₅N₃O₂.1.9HCl.1.2H₂O: C, 51.79; H, 7.49; N, 10.66; Cl, 17.08. found:C, 51.78; H, 7.64; N, 10.35; Cl, 17.07.

15.2,4,6-Trifluoro-N-methyl-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidehydrochloride salt

Dissolve 2,6-dibromopyridine (3.6 g, 15.3 mmol) in anhydrousdichloromethane (90 mL) under nitrogen atmosphere. Cool the reactionmixture to −78° C. Add a solution of n-butyl lithium in hexane veryslowly via a syringe (1.6 M, 10.5 mL, 16.9 mmol). After the addition iscomplete, stir the reaction at −78° C. for 1 hr. Add a solution of4-(methoxy-methyl-aminocarbonyl)-piperidine-1-carboxylic acid tert-butylester (2 g, 7.3 mmol) in anhydrous dichloromethane (10 mL) dropwise tothe reaction mixture. Stir the reaction at −78° C. for 2 hrs., thenallow it to slowly warm to room temperature overnight. Quench thereaction with 0.1 N aqueous NaOH. Dilute the solution withdichloromethane (100 mL), transfer into a separation funnel and shakewith 0.1 N NaOH (60 mL). Separate the organic layer and dry it overanhydrous sodium sulfate. Evaporate the solvent under reduced pressure.Further purify the residue by chromatography on silica gel column(10%-30% ethyl acetate/hexane) to obtain2-bromo-6-(1-t-butoxycarbonylpiperidin-4-ylcarbonyl)-pyridine (2.7 g,quantitative yield). Mass spectrum (ion spray): m/z 370 (M+1).

Heat a mixture of2-bromo-6-(1-t-butoxycarbonylpiperidin-4-ylcarbonyl)-pyridine (152 mg,0.41 mmol), N-methyl-2,4,6-trifluorobenzamide (92.6 mg, 0.49 mmol),Pd₂(dba)₃ (9.2 mg, 0.01 mmol), BINAP (12.4 mg, 0.02 mmol), sodiumt-butoxide (55 mg, 0.57 mmol) in anhydrous toluene (10 mL) at 85° C. for16 hrs. Cool the reaction to room temperature and add another aliquot ofN-methyl-2,4,6-trifluorobenzamide, Pd₂(dba)₃, BINAP and sodiumt-butoxide in the same amount. Re-heat the reaction at 85° C. for 16more hours. Extract the reaction mixture with ethyl acetate and aqueousNaOH (0.1N). Collect and dry the organic layers. Concentrate and purifythe crude product by chromatography (silica gel, 10%-30% ethylacetate/hexane) to obtain2,4,6-trifluoro-N-methyl-N-[6-(1-t-butoxycarbonyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide(86 mg, 44% yield).

Dissolve the2,4,6-trifluoro-N-methyl-N-[6-(1-t-butoxycarbonyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidein 50% trifluoroacetic acid/CH₂Cl₂ (24 mL) and stir for 45 min. Removevolatiles under reduced pressure and extract with ethyl acetate andaqueous NaOH (2M). Combine the organic layers and dry with sodiumsulfate. Concentrate and purify the residue by chromatography (silicagel/6% of (2M NH₃ in methanol)/CH₂Cl₂) to afford2,4,6-trifluoro-N-methyl-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide(77 mg, 85% yield).

Dissolve the2,4,6-trifluoro-N-methyl-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide(77 mg, 0.20 mmol) in methanol (10 mL), add 37% aqueous formaldehyde(0.16 mL, 2.0 mmol), glacial acetic acid (0.34 mL, 6.0 mmol) and NaBH₃CN(21.9 mg, 0.35 mmol). Stir the reaction mixture at room temperature.Extract the mixture with ethyl acetate and aqueous NaOH (2M) to obtain2,4,6-trifluoro-N-methyl-N-[6-(α-hydroxy-(1-methylpiperidin-4-ylcarbonyl)-methyl)-pyridin-2-yl]-benzamide.Dissolve the2,4,6-trifluoro-N-methyl-N-[6-(α-hydroxy-(1-methylpiperidin-4-ylcarbonyl)-methyl)-pyridin-2-yl]-benzamidein anhydrous CH₂Cl₂ (12 mL) and treat under N₂ with Dess-Martin reagent(127 mg, 0.30 mmol) for 1 hr. Extract with ethyl acetate and 2M aqueousNaOH. Collect and dry the organic layers. Concentrate and purify theresidue by chromatography (silica gel/6% of (2M NH₃ in methanol)/CH₂Cl₂)to afford the free amine of the title compound (60.2 mg, 77% yield).Dissolve the free base in methanol (10 mL) and treat with ammoniumchloride (0.032 g). Concentrate and dry under vacuum to obtain the titlecompound. Mass spectrum (ion spray): m/z=392.0 (M+1); ¹H NMR(methanol-d₄): 7.85 (m, 2H), 7.50 (m, 1H), 6.80 (m, 2H), 3.75 (m, 1H),3.52 (d, 2H), 3.47 (s, 3H), 3.20 (t, 2H), 2.94 (s, 3H), 2.03 (d, 2H),1.83 (m, 2H).

16.2,4,6-Trifluoro-N-ethyl-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidehydrochloride salt

Dissolve 2,6-dibromopyridine (5.5 g, 23.2 mmol) in anhydrousdichloromethane (140 mL) under a nitrogen atmosphere. Cool the reactionmixture to −78° C. Add a solution of n-butyl lithium in hexane (1.6 M,15.8 mL, 25.3 mmol) very slowly via a syringe. After the addition iscomplete, stir the reaction at −78° C. for 1 hr. Add a solution of1-methyl-N-methyl-N-methoxy-piperidine-4-carboxamide (2 g, 11 mmol) inanhydrous dichloromethane (10 mL) dropwise to the reaction mixture. Stirthe reaction at −78° C. for 2 hrs, and then allow the mixture to slowlywarm to room temperature overnight. Quench the reaction with 0.1 N NaOH.Dilute the solution with dichloromethane (100 mL), transfer into aseparatory funnel and shake with 2 N NaOH (50 mL). Separate the organiclayer, dry it over anhydrous sodium sulfate, and then evaporate thesolvent under reduced pressure. Further purify the residue bychromatography on asilica gel column (6%, 2M NH₃ in methanol/CH₂Cl₂) toobtain 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine e (2.3 g, 74%yield). Mass spectrum (ion spray): m/z 283 (M+1).

Combine 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridin (189 mg, 0.67mmol), N-ethyl-2,4,6-trifluorobenzamide (162 mg, 0.80 mmol), Pd₂(dba)₃(14.6 mg, 0.016 mmol), BINAP (19.9 mg, 0.032 mmol), sodium t-butoxide(90.2 mg, 0.94 mmol) and anhydrous toluene (10 mL), and heat the mixtureat 85° C. for 16 hr. under a nitrogen atmosphere. Cool the reaction toroom temperature and add additional N-ethyl-2,4,6-trifluorobenzamide,Pd₂(dba)₃, BINAP, sodium t-butoxide in the same amounts. Re-heat thereaction at 85° C. for 16 more hours. Extract with ethyl acetate andaqueous NaOH (0.1N). Collect and dry the organic layers. Concentrate andpurify the residue by chromatography (silica gel, 10%-30% ethylacetate/hexanes) to obtain the free base of the title compound (100 mg,37% yield). Dissolve the free base in methanol (10 mL) and treat withammonium chloride (0.032 g). Concentrate and dry under vacuum to obtainthe title compound. Mass spectrum (ion spray): m/z=406.1 (M+1); ¹H NMR(methanol-d₄): 7.94 (m, 2H), 7.54 (m, 1H), 6.88 (m, 2H), 4.12 (q, 2H),3.86 (m, 1H), 3.77 (d, 2H), 3.18 (t, 2H), 2.94 (s, 3H), 2.15 (d, 2H),1.92 (m, 2H).

17.2,4,6-Trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide

Add 1-chloroethyl chloroformate (0.8 g) into a solution of2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide(0.216 g) in dichloroethane (10 mL) and heat at reflux for 1 hr. Thenadd more 1-chloroethyl chloroformate (1 mL) and heat at refluxovernight. Add methanol (10 mL) to the reaction mixture, concentrate toa small volume, dilute with methanol again, load onto an SCX column (10g), wash with methanol, and elute with 2M NH₃-methanol, evaporate andpurify on a silica gel column (CH₂Cl₂ with 2 M NH₃ in methanol) toobtain the title compound (61 mg). Mass spectrum (electric spray)m/z=364 (M+1); ¹H NMR (CDCl₃): 8.55 (d, J=8.1 Hz, 1H), 7.92 (dd, J=8.0,8.0 Hz 1H), 7.84 (1H, J=8.0 Hz, 1H), 6.81 (m, 3H), 3.89 (m, 1H), 3.12(br d, 2H), 2.81 (m, 2H), 1.85 (m, 2H), 1.74 (br, 2H), 1.61 (m, 2H).

Add 0.17 mL of 1N HCl in ether into a solution of the free base inmethylene chloride-methanol, evaporate the solvent and dry under vacuumto obtain the monohydrochloride salt.

18.2,4,6-Trifluoro-N-[6-(1-ethylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide

Mix2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide(26 mg), acetaldehyde (42 mg), sodium cyanoborohydride (10 mg) andtrifluoroacetic acid (16.4 mg) in methanol (2 mL) in a sealed tube andheat in an oil bath at 90° C. overnight. Dilute with methanol and loadon a SCX column (10 g), wash with methanol, elute the product with 2MNH₃-methanol, evaporate, purify on a silica gel column (4 g, solvent:dichloromethane-2M NH₃ in methanol, gradient) to obtain the titlecompound (8.4 mg). Mass spectrum (electrospray) m/z=392 (M+1); ¹H NMR(CDCl₃): 8.51 (d, 1H), 8.42 (br, 1H), 7.92 (t, 1H), 7.82 (dd, 1H), 6.84(m, 2H), 3.63 (m, 1H), 3.02 (m, 2H), 2.44 (m, 2H), 2.04 (m, 2H), 1.87(m, 4H), 1.60 (m, 5H), 1.11 (t, J=6.8 Hz, 3H).

Dissolve the free base (8.4 mg) in dichloromethane-methanol and add 0.02mL of 1N HCl in ether, evaporate and dry in vacuum to give thehydrochloride salt.

19.2,4,6-Trifluoro-N-[6-(1-propylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide

Mix2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide(50 mg), propionaldehyde (80 mg), sodium triacetoxyborohydride (38 mg)and acetic acid (21 mg) with dichloromethane (5 mL) and stir for 1.5hrs. Dilute with methanol and load on a SCX column (10 g), wash withmethanol, elute the product with 2M NH₃-methanol. Purify the product ona silica gel column (10 g, dichloromethane/2M NH₃ in methanol, gradient)to obtain the title compound as a free base (26 mg). Mass spectrum(electrospray) m/z=406 (M+1); ¹H NMR (CDCl₃): 8.52 (d, 1H), 8.38 (br,1H), 7.92 (t, 1H), 7.82 (dd, 1H), 6.82 (m, 2H), 3.61 (br, 1H), 3.00 (m,2H), 2.34 (m, 2H), 2.11 (m, 2H), 1.87 (m, 3H), 1.60 (m, 5H), 0.90 (t,J=7.3 Hz, 3H).

Dissolve the free base (26 mg) in dichloromethane-methanol and add 0.064mL of 1N HCl in ether, evaporate and dry under vacuum to obtain thehydrochloride salt.

20.2,4,6-Trifluoro-N-[6-(1-cyclopropylmethyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidedihydrochloride salt

Combine2,4,6-trifluoro-N-[6-(piperidin-4-ylcarbonyl)pyridin-2-yl]benzamide(0.05 g, 0.138 mmol), cyclopropylmethanal (0.10 g, 1.38 mmol) anddichloromethane (5 mL), and stir at ambient temperature. After 15minutes, add glacial acetic acid (0.02 mL, 0.35 mmol) followed bysodium-triacetoxyborohydride (0.038 g, 0.18 mmol) with stirring. After 3hrs., dilute the reaction mixture with methanol (5 mL) and load on anSCX column (10 g). Wash the column with methanol, elute with 2Mammonia/methanol, and concentrate the eluent. Purify the residue byflash chromatography, eluting with 10% ammonia/methanol indichloromethane, to obtain the free base of the title compound (0.045 g,77%). Dissolve the free base in dichloromethane (5 mL), treat with 1Mhydrogen chloride in diethylether (0.25 mL), and concentrate the mixtureto obtain the dihydrochloride salt. M.p.=140° C.; HRMS: Obs. m/z418.1743; Calc. m/z 418.1742; ¹H NMR (CDCl₃): 11.51 (bs, 1H), 10.34 (bs,1H), 8.38 (m, 1H), 8.11 (m, 1H), 7.78 (d, 1H), 7.42 (m, 2H), 3.79 (m,1H), 3.64 (m, 2H), 2.98 (m, 4H), 2.17 (m, 2H), 1.99 (m, 2H), 1.13 (m,1H), 0.65 (m, 2H), 0.39 (m, 2H).

Preparations 3. N-Methylisonipecotic acid

Load isonipicotic acid (1 kg, 7.74 mol), water (10 L), formaldehyde (37%solution in water, 720 g, 8.87 mol, 1.15 eq.) and wet Pd/C catalyst(10%; 55% paste, 100 g) into a stainless steel hydrogenation reactor.Pressurize the reactor with H₂ (3 bar) and stir the reaction mixtureovernight at 200-300 rpm at 16-25° C. Stop the reaction and filter offthe catalyst. Wash the filtrate with water (500 ml) and concentrateunder vacuum. Distill off the remaining water from the residue usingethanol (2×1 L). Dry the solid overnight under vacuum at 50° C. toobtain the title product as an off-white solid (1087 g, 98.1% yield).

4. N-Methylisonipecotyl chloride hydrochloride

Suspend N-methylisonipicotic acid (365 g, 2.55 mol) in CH₂Cl₂ (3500 ml)and add a catalytic quantity of DMF (2 ml). Add oxalyl chloride (435 g,3.42 mol, 1.35 eq.) to the reaction mixture maintaining the temperatureat 20° C. Heat the suspension under reflux for 2 hrs. Cool the reactionmixture and concentrate on a rotary evaporator. Resuspend the residue intoluene (1000 ml), evaporate and dry under vacuum to yield the titleproduct (489 g, 96%) as an off-white solid residue, which is usedwithout further purification in the next reaction step.

5. N,N′-Dimethyl-N-methylisonipecotamide

Resuspend N-methylisonipecotyl chloride hydrochloride (489 g, 2.54 mol)in anhydrous THF (5000 mL) and cool the suspension to 0-5° C. Add asolution of dimethylamine in THF (2M, 2500 ml, 2 eq.) and triethylamine(775 g, 3 eq.) dropwise to the reaction mixture maintaining thetemperature below 7° C. Stir the suspension for 3 hrs. at thistemperature and then allow the reaction mixture to warm to 20° C.overnight. Then cool the reaction mixture to 5° C. and 30% NaOH (600 mL)and add CH₂Cl₂ (2 L). Separate the organic layer from the sticky solidthat is formed and redissolve the solid in water (2 L). Extract thesolution with CH₂Cl₂ (2 L). Combine the organic fractions, concentrateto about 3500 mL, and wash twice with water (500 mL). Dry the organiclayer with Na₂SO₄, filter, and concentrate to dryness. Dry the red oilunder vacuum at room temperature to produce the title product (378.7 g,90% yield). Treat with ether and evaporate to dryness to obtain theproduct as a solid.

6. 2-Bromo-6-(1-methylpiperid-4-ylcarbonyl)-pyridine

Cool methyl-tert-butyl ether (MTBE) (50 mL) (T_(mass)=−75° C.) under anitrogen atmosphere, and add n-butyl litium (2.5M in n-hexane, 35 mL,0.875 mol) to give a white suspension. Add 2,6-Dibromopyridine (20.9 g,0.088 mol) in MTBE (210 mL) dropwise to the suspension at a rate thatmaintains the T_(mass) under −65° C. (40 min). Stir the resulting yellowheterogeneous solution at −70° C. for 20 min. to produce a greenhomogeneous solution. Then add N′,N-dimethyl-N-methylisonipecotamide (10g, 0.0587 mol) in MTBE (100 mL) dropwise at a rate that maintains theT_(mass) under −65° C. (20 min). After the addition is completed,agitate the mixture at −75° C. for 1 hour. Quench the reaction mixturewith saturated ammonium chloride (30 mL) at 0-10° C. Neutralize thereaction mixture (pH=7) with 37% HCl (15 mL) and add additional water(50 mL). Decant the aqueous phase and extract with CH₂Cl₂ (3×500 mL).Combine the organic layers and wash with acidic water (pH=2) (3×500 mL).Then basify the aqueous phase with 30% NaOH (pH=12) and extract themixture with ethyl acetate (2×500 mL). Combine the organic layers, drywith MgSO₄, concentrate under reduced pressure, and then vacuum dry atroom temperature to provide the title product as an oil (16 g, 96%yield). Mass spectrum (electrospray) m/z=283-285 (M+1); ¹H NMR: (400MHz, CHLOROFORM-D) ppm 1.76 (m, 2 H) 1.91 (m, 2 H) 2.14 (m, 2 H) 2.30(s, 3 H) 2.90 (d, J=11.85 Hz, 2 H) 3.71 (m, 1 H) 7.62 (d, J=7.54 Hz, 1H) 7.67 (t, J=7.54 Hz, 1H) 7.95 (d, J=7.54 Hz, 1H); ¹³C-NMR: (100.61MHz, Chloroform-D) ppm 28.08; 41.68; 46.36; 55.08; 121.26; 131.61;139.25; 141.24; 153.59; 202.23.

7. 2-Amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine

Load 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-piperidine (20 g, 70.67mmol, 1 eq) in 73.6 ml of 7M NH₃/ethylene glycol (530 mmol, 7.5 eq) intoa 130 ml pressure autoclave, and add Cu₂O (101 mg, 0.706 mmol, 0.01 eq)as a catalyst. Seal the autoclave and heat the reaction mixture to 85°C. at about 50 psi (345 kPa) for 20 hrs. Cool the reaction mixture toroom temperature, transfer the organic layer to a 250 ml flask, andplace the flask under reduce pressure to remove ammonia. Add water (70mL) and of 30% NaOH (38 mL) and then extract the mixture with methylt-butyl ether (MTBE)(5×100 ml). Combine the organic fractions and thendry with MgSO4, filter, and concentrate under reduce pressure to obtaincrude 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (18.5 g).

Resuspend the crude 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine(14.5 g, 66.2 mmol) in ethanol (30 mL), add 2.5M HCl/ethanol (100 mL),stir the mixture for 30 minutes, and then remove the solvent underreduce pressure. Resuspend the resulting solid in 125 ml isopropanol andheat under reflux for 30 minutes. Cool the reaction mixture to roomtemperature, filtered-off the precipitate, rinse with 20 ml isopropanol,and dry under vacuum at 50° C. to obtain2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine 2HCl (11 g, 63%yield corrected by HPLC % w/w).

Resuspend the 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine 2HCl(129.5 g) in ethyl acetate (100 mL) and add 10M NaOH (50 mL) and water(50 mL) to neutralize the suspension. Separate the organic layer andextract the aqueous phase with ethyl acetate (2×150 mL). Combine theorganic layers, dry with MgSO₄, filter, and concentrate under reducepressure to obtain the title product (21 g).

Examples 21.2,4,6-Trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide

Add triethylamine (10.67 mL, 76.70 mmol, 2.4 eq) to a solution of2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (7 g, 31.96 mmol, 1eq) in anhydrous THF (100 mL) under a nitrogen atmosphere. Add2,4,6-triflubenzoylchloride (7.46 g, 5 mL, 38.35 mmol, 1.20 eq) dropwiseat room temperature. After 2 hrs., add additional2,4,6-triflubenzoylchloride (0.75 mL, 0.15 eq) and triethylamine (1.32mL, 0.3 eq) to the reaction mixture and agitate the mixture for anadditional 3 hrs. Quench the reaction with distilled water (10 mL) and30% NaOH (15 mL). Stir the resulting biphasic system for 1 hour and thenseparate the phases. Extract the organic fraction by adding H₂O (75 mL)and acetic acid (12 mL), followed by cyclohexane (70 mL). Wash theorganic fraction with H₂O (50 mL) containing acetic acid (1 mL). Combineall the aqueous fractions and washes and neutralize the mixture with 30%NaOH (15 mL). Extract with methyl-tert-butyl ether (MTBE) (3×50 mL).Combine the organic fractions and dry with MgSO₄, filter, concentrateunder reduce pressure, and vacuum dry at room temperature, to obtain thetitle compound as a light-brown solid (11.031 g, 91% yield). Massspectrum (Electrospray) m/z=378 (M+1); ¹H NMR (250 MHz, Chloroform-D)ppm 1.54 (m, 2 H) 2.02 (m, 2 H) 2.13 (t, J=11.48 Hz, 2 H) 2.29 (s, 3 H)2.80 (m, J=11.96 Hz, 1 H) 3.56 (m, 1 H) 4.26 (d, J=7.87 Hz, 1 H) 6.17(d, J=8.50 Hz, 1 H) 6.75 (m, 2 H) 7.45 (t, J=7.87 Hz, 1 H) 7.53 (m, 1 H)7.95 (s, 1 H); ¹³C-NMR: (62.90 MHz, Chloroform-D) ppm 202.78; 162.6 (dmC—F-couplings); 162.0 (m C—F-couplings); 160.1 (m C—F-couplings); 158.1;150.0; 139.7; 119.3; 117.9; 110.2 (m C—F-couplings); 100.9 (mC—F-couplings); 55.2; 46.5; 41.9; 28.1

22.2,4,6-Trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamidemono-hydrochloride salt

Dissolve2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide—freebase (5 g, 23.26 mmol) in isopropanol (50 mL) at room temperature andadd a solution of 3.3 M diethylether/HCl (8 mL). Heat the reactionmixture under reflux for 30 minutes. Cool the reaction mixture to roomtemperature and agitate for 2 hrs. Filter the resulting whiteprecipitate and rinse with isopropanol (5 mL). Dry the residual solidunder reduce pressure at 40° C. overnight to obtain the title compound(5.12 g, 93% yield). M.p. 223-224° C. (sublimation); ¹H NMR (400 MHz,d6-DMSO) d ppm 1.94 (m, 2 H) 2.14 (m, J=11.15 Hz, 2 H) 2.74 (s, 3 H)2.99 (m, J=9.19 Hz, 2 H) 3.49 (m, J=11.15 Hz, 2 H) 3.77 (m, 1 H) 7.41(t, J=8.71 Hz, 2 H) 7.78 (d, J=7.43 Hz, 1 H) 8.10 (t, J=7.92 Hz, 1 H)8.37 (d, J=6.85 Hz, 1 H) 10.50 (s, 1 H) 11.51 (s, 1 H); ¹³C-NMR: (100.61MHz, Chloroform-D) ppm 200.7; 130.6-158.0 (m, C—F-couplings); 150.4;150.1; 140.2; 118.5; 118.2; 111.9; 101.3 (t, C—F couplings); 52.8; 42.6;25.2

23.2,4,6-Trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamidehemi-succinate salt

Add succinic acid (0.25 g, 2.148 mmol, 0.5 eq) to a solution of2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide—freebase (1.62 g, 4.297 mmol, 1 eq) in acetone (16.2 mL), at roomtemperature. Warm the solution under reflux for 30 minutes. Cool thesolution to room temperature and filter off the resulting whiteprecipitate. Rinse the precipitate with acetone (0.2 mL) and dry undervacuum at 50° C. for 16 hours to provide the title compound (1.5 g, 80%yield). M.p. 198.5° C.; mass spectrum (Electrospray) m/z=495.45

The following examples are prepared by combinatorial chemistrytechniques as follows:

Examples 24-54

Combine R-acid (300 μL of 0.5M solution in dimethylformamide (DMF)),HATU (57 mg, 0.15 mmol), collidine (19 μL, 0.15 mmol),2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine and DMF (1.5 mL),and agitate for 48 hr. Dilute the reaction mixture with 10% acetic acidin methanol (0.5 mL). Load the resulting reaction mixture onto a 2 g SCXcolumn. Wash the column thoroughly with methanol and then elute with 1 Mammonia in methanol. Concentrate the eluent and further purify theproduct by high-throughput mass guided chromatography. This procedure isrepeated in parallel for examples 24-54.

Examples 55-58

Heat R-acid chloride (300 μL of 0.5M solution in pyridine) to 55° C.,add 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of 0.5Msolution in pyridine), and continue heating the reaction mixture for 24hr. Concentrate the reaction mixture and then dilute with 10% Aceticacid in methanol (0.5 mL) and methanol (0.5 mL). Load the resultingreaction mixture directly onto a 2 g SCX column. Thoroughly wash thecolumn with methanol and then elute the column with 1 M ammonia inmethanol. Concentrate the eluent and then further purify the product byhigh-throughput mass guided chromatography. This procedure is repeatedin parallel for examples 55-58.

Examples 59-71

Heat 2-amino-(6-(1-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of0.5M solution in pyridine) to 55° C. then add R-acid chloride (0.10mmol), heat for 2 hr. Concentrate the reaction mixture and then dilutewith 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL). Loadthe resulting reaction mixture directly onto a 2 g SCX column.Thoroughly wash the column with methanol and then elute the column with1 M ammonia in methanol. Concentrate the eluent and then further purifythe product by high-throughput mass guided chromatography. Thisprocedure is repeated in parallel for examples 59-71.

Recombinant chemistry compounds are characterized by liquidchromatography/mass spectroscopy on a Shimadzu QP8000™. Examples 24-45and 55-58 are run with a Metachem™ C18 column (monochrom 3 micron,2.5×25 cm) using a 10-90% solvent B gradient in 4.5 min., where solventA is 0.1% trifluoroacetic acid in water and solvent B is 0.1%trifluoroacetic acid in acetonitrile. Examples 46-54 and 59-71 are runwith a Metachem™ C18 column (monochrom 5 micron, 4.6×50 cm) using a10-80% solvent B gradient in 9 min., where solvent A is 0.1%trifluoroacetic acid in water and solvent B is 0.08% trifluoroaceticacid in acetonitrile.

24 N-[6-(1-Methyl- piperidin-4- ylcarbonyl)-pyridin-2- yl]-thiophene-2-amide

LCMS Rf 2.871 min at 254 nm, 2.871 min at 190 nm, m/e 330 (M + 1). 25N-[6-(1-Methyl- piperidin-4- ylcarbonyl)-pyridin-2- yl]-furan-2-amide

LCMS Rf 2.454 min at 254 nm, 2.454 min at 190 nm, m/e 314 (M + 1). 262-Chloro-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 3.080 min at 254 nm, 3.080 min at 190 nm, m/e 358 (M + 1). 27N-[6-(1-Methyl- piperidin-4- ylcarbonyl)-pyridin-2- yl]-furan-3-amide

LCMS Rf 2.448 min at 254 nm, 2.448 min at 190 nm, m/e 314 (M + 1). 283,4-Difluoro-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 4.47 min at 254 nm, m/e 360 (M + 1). 29 N-[6-(1-Methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-isonicotinamide

LCMS Rf 2.890 min at 254 nm, 2.890 min at 190 nm, m/e 325 (M + 1). 302-Methyl-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 3.092 min at 254 nm, 3.092 min at 190 nm, m/e 338 (M + 1). 312-Bromo-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 3.132 min at 254 nm, 3.132 min at 190 nm, m/e 402 (M + 1). 322-trifluoromethoxy-N- [6-(1-methyl- piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 2.771 min at 254 nm, 2.771 min at 190 nm, m/e 330 (M + 1). 332-Fluoro-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-isonicotinamide

LCMS Rf 2.669 min at 254 nm, 2.669 min at 190 nm, m/e 343 (M + 1). 344-Chloro-2-methoxy- N-[6-(1-methyl- piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 3.665 min at 254 nm, 3.664 min at 190 nm, m/e 387 (M + 1). 352-Ethoxy-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 3.519 min at 254 nm, 3.520 min at 190 nm, m/e 367 (M + 1). 362-Phenoxy-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 3.841 min at 254 nm, 3.838 min at 190 nm, m/e 415 (M + 1). 372-Methoxy-5-chloro- N-[6-(1-methyl- piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 3.661 min at 254 nm, 3.666 min at 190 nm, m/e 387 (M + 1). 382-Methoxy-4- methylsulfanyl-N-[6- (1-methylpiperidin-4-ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 3.683 min at 254 nm, 3.692 min at 190 nm, m/e 399 (M + 1). 39N-[6-(1-Methyl- piperidin-4- ylcarbonyl)-pyridin-2- yl]-2,3-Dihydrobenzofuran-7- amide

LCMS Rf 3.381 min at 254 nm, 3.381 min at 190 nm, m/e 365 (M + 1). 402-Benzyloxy-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 4.086 min at 254 nm, 4.089 min at 190 nm, m/e 429 (M + 1). 412-Propoxy-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 3.811 min at 254 nm, 3.813 min at 190 nm, m/e 381 (M + 1). 422,2-Difluoro-N-[6-(1- methyI-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzo[1,3]dioxole-4- amide

LCMS Rf 3.531 min at 254 nm, 3.534 min at 190 nm, m/e 403 (M + 1). 432-(2-Methoxy- ethoxy)-4-methoxy-N- [6-(1-methyl- piperidin-4-ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 3.552 min at 254 nm, 3.556 min at 190 nm, m/e 427 (M + 1). 442-Methoxy-5-bromo- N-[6-(1-methyl- piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 3.742 min at 254 nm, 3.742 min at 190 nm, m/e 432 (M + 1). 452-(4,6-Dimethoxy- pyrimidin-2-yloxy)-N- [6-(1-methyl- piperidin-4-ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 3.428 min at 254 nm, 3.425 min at 190 nm, m/e 477 (M + 1). 462-Ethoxy-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-nicotinamide

LCMS Rf 1.56 min at 254 nm, m/e 368 (M + 1). 47 2-Phenoxy-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-nicotinamide

LCMS Rf 1.61 min at 254 nm, m/e 416 (M + 1). 48 3-Acetyl-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-thiazolidine-4- amide

LCMS Rf 1.23 min at 254 nm, m/e 376 (M + 1). 49 2-Phenylsulfanyl-N-[6-(1-methyl- piperidin-4- ylcarbonyl)-pyridin-2- yl]-nicotinamide

LCMS Rf 1.59 min at 254 nm, m/e 432 (M + 1). 50 2-(2,2,2-Trifluoroethoxy)-5- methoxy-N-[6-(1- methyl-piperidin-4-ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.69 min at 254 nm, m/e 451 (M + 1). 51 2-Methoxy-6-methyl-N-[6-(1-methyl- piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.50 min at 254 nm, m/e 367 (M + 1). 52 4-Methoxycarbonyl-N-[6-(1-methyl- piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.53 min at 254 nm, m/e 381 (M + 1). 53 N-[6-(1-Methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]- Cyclobutylformamide

LCMS Rf 1.31 min at 254 nm, m/e 301 (M + 1). 54 2-(2-Chloro-1,1,2-trifluoroethoxy)-N-[6- (1-methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 1.64 min at 254 nm, m/e 455 (M + 1). 55 N-[6-(1-Methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-butanamide

LCMS Rf 2.23 min at 254 nm, m/e 290 (M + 1). 56 N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]- cyclohexylformamide

LCMS Rf 4.23 min at 254 nm, m/e 330 (M + 1). 57 N-[6-(1-Methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-3-phenyl- propanamide

LCMS Rf 4.86 min at 254 nm, m/e 352 (M + 1). 58 2,6-Difluoro-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 4.05 min at 254 nm, m/e 360 (M + 1). 59 2-Chloro-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.47 min at 254 nm, m/e 357 (M + 1). 60 2,5-Difluoro-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.52 min at 254 nm, m/e 359 (M + 1). 61 3,4-Difluoro-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.54 min at 254 nm, m/e 359 (M + 1). 62 2-Trifluoromethyl-4-fluoro-N-[6-(1- methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.57 min at 254 nm, m/e 409 (M + 1). 63 2-Fluoro-6-trifluoromethyl-N-[6- (1-methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 1.60 min at 254 nm, m/e 409 (M + 1). 64 2,3,4-Trifluoro-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.57 min at 254 nm, m/e 377 (M + 1). 65 2,4,5-Trifluoro-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.56 min at 254 nm, m/e 377 (M + 1). 67 3-Chloro-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-thiophene-2- amide

LCMS Rf 1.67 min at 254 nm, m/e 363 (M + 1). 68 2,6-Dichloro-N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-benzamide

LCMS Rf 1.57 min at 254 nm, m/e 391 (M + 1). 69 2-Fluoro-4-trifluoromethyl-N-[6- (1-methyl-piperidin-4- ylcarbonyl)-pyridin-2-yl]-benzamide

LCMS Rf 1.67 min at 254 nm, m/e 409 (M + 1). 70 N-[6-(1-methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]- Cyclopentylformamide

LCMS Rf 3.06 min at 254 nm, m/e 315 (M + 1). 71 N-[6-(1-Methyl-piperidin-4- ylcarbonyl)-pyridin-2- yl]-nicotinamide

LCMS Rf 2.5 min at 254 nm, m/e 324 (M + 1).

Preparations

7. 1-Methyl-4-(pyrrolidin-1-yl-carbonyl)-piperidine

Add oxalyl chloride (5.08 mL, 0.058 mol) dropwise to a suspension of1-methyl-4-carboxypiperidine HCl (10 g, 0.056 mol) in THF (100 mL) inthe presence of a catalytic amount of DMF (0.1 mL) at room temperature.Stir for 1 hr. and then heat the mixture at reflux until gas emissionstops (about 1 hr.). Cool the white suspension to 5° C. and add asolution of pyrrolidine (7.92 g, 0.111 mol) and triethylamine (16.9 g,0.167 mol) dropwise over 30 min at a temperature between 5 and 13° C.Stir the suspension for 30 min. at 10° C. and then warm to roomtemperature. Quench the reaction mixture by adding 30% NaOH (20 mL, 0.2mol) and water (10 mL). Decant the aqueous layer and extract with THF(200 mL). Combine the organic layers, dry over Na₂CO₃, and evaporateunder vacuum at 40° C. Solubilize the resulting oil in cyclohexane (200mL). Evaporate under reduced pressure at 40° C. to give a white solid(11 g). 1-Teat the white solid (11 g) under reflux in cyclohexane (50mL) until completely dissolved. Cool the solution to room temperatureand stir at room temperature for 2 hr. Filter the suspension wash thecrystals with cyclohexane (10 mL). Dry the white crystals under reducedpressure at 40° C. to provide the title intermediate (7.76 g, 75%yield).

8. 2-Bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine

Add a solution of n-butyllithium (1.9M in n-hexane, 4 ml, 7.6 mmol) to asolution of 2,6-dibromopyridine (1.81 g, 7.64 mmol) in MTBE (20 mL)dropwise under nitrogen, over 20 min., maintaining the temperaturebetween −72 and −67° C. Stir the yellow heterogeneous solution at −70°C. for 20 min. to provide a green homogeneous solution. Add a solutionof 1-methyl-4-(pyrrolidin-1-yl-carbonyl)piperidine (1 g, 5.09 mmol) in10 mL MTBE dropwise over 20 min., maintaining the temperature below −69°C. Stir the yellow mixture at −75° C. for 1 hr. Quench the reactionmixture with a saturated solution of ammonium chloride (5 mL) between 0and 10° C. Acidify the mixture to pH 2 with fuming HCl (2 mL). Extractthe organic layer. Wash the aqueous phase with MTBE (50 mL), make theaqueous layer basic with a solution of 30% NaOH, and extract with ethylacetate (2×50 mL). Combine the organic layers, dry over MgSO₄, andconcentrate under reduced pressure at 40° C. to provide the titleintermediate as an oil (1.23 g, 85% yield).

The compounds of this invention are useful for increasing activation ofthe 5-HT_(1F) receptor. An increase in the activation of the 5-HT_(1F)is useful for treating a variety of disorders which have been linked todecreased neurotransmission of serotonin in mammals, e.g., migraineheadaches. See U.S. Pat. No. 5,708,008 demonstrating the nexus betweenactivation of the 5-HT_(1F) receptor and migraine. To demonstrate theuse of the compounds of the present invention in the treatment ofmigraine, their ability to bind to the 5-HT_(1F) receptor subtype wasdetermined. The ability of the compounds of this invention to bind tothe 5-HT_(1F) receptor subtype was measured essentially as described inN. Adham, et al., Proceedings of the National 15 Academy of Sciences(USA), 90:408-412, 1993.

Membrane Preparation:

Membranes were prepared from transfected Ltk-cells (transfected with thehuman 5-HT_(1F) receptor sequence) which were grown to 100% confluency.The cells were washed twice with phosphate-buffered saline, scraped fromthe culture dishes into 5 mL of ice-cold phosphate-buffered saline, andcentrifuged at 200×g for 5 minutes at 4° C. The pellet was resuspendedin 2.5 mL of ice-cold Tris buffer (20 mM Tris HCl, pH 7.4 at 23° C., 5mM EDTA) and homogenized with a Wheaton tissue grinder. The lysate wassubsequently centrifuged at 200×g for 5 minutes at 4° C. to pellet largefragments which were discarded. The supernatant was collected andcentrifuged at 40,000×g for 20 minutes at 4° C. The resulting pellet waswashed once in ice-cold Tris wash buffer and resuspended in a finalbuffer containing 50 mM Tris HCl and 0.5 mM EDTA, pH 7.4 at 23° C.Membrane preparations were kept on ice and utilized within two hours forthe radioligand binding assays. Protein concentrations were determinedby the method of Bradford. Anal. Biochem., 72:248-254, 1976.

Radioligand Binding:

[³H] 5-HT binding was performed using slight modifications of the5-HT_(1D) assay conditions reported by Herrick-Davis and Titeler (J.Neurochem., 50:1624-1631, 1988) with the omission of masking ligands.Radioligand binding studies were achieved at 37° C. in a total volume of250 μL of buffer (50 mM Tris, 10 mM MgCl₂, 0.2 mM EDTA, 10 μM pargyline,0.1% ascorbate, pH 7.4 at 37° C.) in 96 well microtiter plates.Saturation studies were conducted using [³H] 5-HT at 12 differentconcentrations ranging from 0.5 nM to 100 nM. Displacement studies wereperformed using 4.5-5.5 nM [³H] 5-HT. The binding profile of drugs incompetition experiments was accomplished using 6-12 concentrations ofcompound. Incubation times were 30 minutes for both saturation anddisplacement studies based upon initial investigations which determinedequilibrium binding conditions. Nonspecific binding was defined in thepresence of 10 μM 5-HT. Binding was initiated by the addition of 50 μLmembrane homogenates (10-20 μg). The reaction was terminated by rapidfiltration through presoaked (0.5% poylethyleneimine) filters using 48RBrandel Cell Harvester (Gaithersburg, Md.). Subsequently, filters werewashed for 5 seconds with ice cold buffer (50 mM Tris HCl, pH=7.4 at 4°C.), dried and placed into vials containing 2.5 mL Readi-Safe (Beckman,Fullerton, Calif.) and radioactivity was measured using a Beckman LS5000TA liquid scintillation counter. The efficiency of counting of [³H]5-HT averaged between 45-50%. Binding data was analyzed bycomputer-assisted nonlinear regression analysis (Accufit and Accucomp,Lunden Software, Chagrin Falls, Ohio). IC₅₀ values were converted to K,values using the Cheng-Prusoff equation. Biochem. Pharmacol.,22:3099-3108 (1973). All experiments were performed in triplicate.Representative compounds of the present invention were found to havehigh affinity for the 5-HT_(1F) receptor as measured by the proceduredescribed above, as for example K_(i)'s of less than or equal to 300 nM.Preferred compounds of the present invention have K_(i)'s of less thanor equal to 100 nM. A yet more preferred embodiment provides compoundshaving a K_(i) of less than or equal to 50 nM.

Selectivity for the 5-HT_(1F) Receptor

Compounds of the prevent invention are relatively selective for the5-HT_(1F) receptor, particularly in comparison to other 5-HT receptorsubtypes, specifically other receptors in the 5-HT₁ subclass, as forexample, but without limitation, the 5-HT_(1A), 5-HT_(1B), 5-HT_(1D),and 5-HT_(1E) receptor subtypes. Affinity for these other receptorsubtypes can readily be determined by slight modification of the abovedescribed radioligand receptor binding assays using cells transfectedwith the desired receptor subtype in place of cells transfected with the5-HT_(1F) receptor subtype. The binding affinities of representativecompounds of the present invention were determined by such assays andwere found to be selective for the 5-HT_(1F) receptor; that is theaffinities of the compounds for the 5-HT_(1F) receptor were on thewhole, higher than for other receptor subtypes, particular for the5-HT_(1B) and 5-HT_(1D) receptor subtypes.

Measurement of cAMP Formation

As was reported by R. L. Weinshank, et al., WO93/14201, the 5-HT_(1F)receptor is functionally coupled to a G-protein as measured by theability of serotonin and serotonergic drugs to inhibit forskolinstimulated cAMP production in NIH3T3 cells transfected with the5-HT_(1F) receptor. Adenylate cyclase activity was determined usingstandard techniques. A maximal effect is achieved by serotonin. AnE_(max) is determined by dividing the inhibition of a test compound bythe maximal effect and determining a percent inhibition. N. Adham, etal., supra,; R. L. Weinshank, et al., Proceedings of the NationalAcademy of Sciences (USA), 89:3630-3634, 1992; and the references citedtherein.

Human 5-HT_(1F) receptor transfected NIH3T3 cells (estimated B_(max)from one point competition studies=488 fmol/mg of protein) wereincubated in DMEM, 5 mM theophylline, 10 mM HEPES(4-[2-hydroxyethyl]-1-piperazineethanesulfonic acid) and 10 μM pargylinefor 20 minutes at 37° C., 5% CO₂. Drug dose-effect curves were thenconducted by adding 6 different final concentrations of drug, followedimmediately by the addition of forskolin (10 μM). Subsequently, thecells were incubated for an additional 10 minutes at 37° C., 5% CO₂. Themedium was aspirated and the reaction was stopped by the addition of 100mM HCl. To demonstrate competitive antagonism, a dose-response curve for5-HT was measured in parallel, using a fixed dose of methiothepin (0.32μM). The plates were stored at 4° C. for 15 minutes and then centrifugedfor 5 minutes at 500×g to pellet cellular debris, and the supernatantwas aliquoted and stored at −20° C. before assessment of cAMP formationby radioimmunoassay (cAMP radioimmunoassay kit; Advanced Magnetics,Cambridge, Mass.). Radioactivity was quantified using a Packard COBRAAuto Gamma counter, equipped with data reduction software.Representative compounds of the present invention were tested and foundto be agonists of the 5-HT_(1F) receptor in the cAMP assay describedabove.

Protein Extravasation Assay

The following test was performed to determine the ability of compoundsof the present invention to inhibit protein extravasation, which test isalso a functional assay for the neuronal mechanism of migraine.

Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles RiverLaboratories (225-325 g) were anesthetized with sodium pentobarbitalintraperitoneally (65 mg/kg or 45 mg/kg respectively) and placed in astereotaxic frame (David Kopf Instruments) with the incisor bar set at−3.5 mm for rats or −4.0 mm for guinea pigs. Following a midline sagitalscalp incision, two pairs of bilateral holes were drilled through theskull (6 mm posterially, 2.0 and 4.0 mm laterally in rats; 4 mmposteriorly and 3.2 and 5.2 mm laterally in guinea pigs, all coordinatesreferenced to bregma). Pairs of stainless steel stimulating electrodes,insulated except at the ends (Rhodes Medical Systems, Inc.), werelowered through the holes in both hemispheres to a depth of 9 mm (rats)or 10.5 mm (guinea pigs) from dura.

The femoral vein was exposed and a dose of the test compound wasinjected intravenously (1 mL/kg). Approximately 7 minutes later, a 50mg/kg dose of Evans Blue, a fluorescent dye, was also injectedintravenously. The Evans Blue complexed with proteins in the blood andfunctioned as a marker for protein extravasation. Exactly 10 minutespost-injection of the test compound, the left trigeminal ganglion wasstimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msecduration) with a Model 273 potentiostat/galvanostat (EG&G PrincetonApplied Research).

Fifteen minutes following stimulation, the animals were killed andexsanguinated with 20 mL of saline. The top of the skull was removed tofacilitate the collection of the dural membranes. The membrane sampleswere removed from both hemispheres, rinsed with water, and spread flaton microscopic slides. Once dried, the tissues were coverslipped with a70% glycerol/water solution.

A fluorescence microscope (Zeiss) equipped with a grating monchromatorand a spectrophotometer was used to quantify the amount of Evans Bluedye in each sample. An excitation wavelength of approximately 535 nm wasutilized and the emission intensity at 600 nm was determined. Themicroscope was equipped with a motorized stage and also interfaced witha personal computer. This facilitated the computer-controlled movementof the stage with fluorescence measurements at 25 points (500 μm steps)on each dural sample. The mean and standard deviation of themeasurements were determined by the computer.

The extravasation induced by the electrical stimulation of thetrigeminal ganglion was an ipsilateral effect (i.e. occurs only on theside of the dura in which the trigeminal ganglion was stimulated). Thisallows the other (unstimulated) half of the dura to be used as acontrol. The ratio of the amount of extravasation in the dura from thestimulated side compared to the unstimulated side was calculated. Salinecontrols yielded a ratio of approximately 2.0 in rats and 1.8 in guineapigs. In contrast, a compound which effectively prevented theextravasation in the dura from the stimulated side would have a ratio ofapproximately 1.0. A dose-response curve was generated and the dose thatinhibited the extravasation by 50% (ID₅₀) was approximated.Representative compounds of the present invention were assayed by theabove procedure and were found to significantly inhibit neuronal proteinextravasation.

Rabbit Saphenous Vein Contraction

Representative compounds of the present invention were tested in arabbit saphenous vein contraction assay to measure their ability tomediate vasoconstriction.

Male New Zealand White rabbits (3-6 lbs) (Hazleton, Kalamazoo, Mich.)were sacrificed by a lethal dose of sodium pentobarbital (325 mg)injected into the ear vein. Tissues were dissected free of connectivetissue, cannulated in situ with polyethylene tubing (PESO, outsidediameter=0.97 mm) and placed in petri dishes containing modified Kreb'ssolution (described infra). The tips of two 30-gauge stainless steelhypodermic needles bent into an L-shape were slipped into thepolyetylene tubing. Vessels were gently pushed from the cannula onto theneedles. The needles were then separated so that the lower one wasattached with thread to a stationary glass rod and the upper one wastied with thread to the transducer.

Tissues were mounted in organ baths containing 10 mL of modified Krebs'solution of the following composition: 118.2 mMol NaCl, 4.6 mMol KCl,1.6 mMol CaCl₂.H₂O, 1.2 mMol KH₂PO₄, 1.2 mMol MgSO₄, 10.0 mMol dextroseand 24.8 mMol NaHCO₃. Tissue bath solutions were maintained at 37° C.and aerated with 95% O₂ and 5% CO₂. An initial optimum resting force of1 gm was applied to the saphenous vein. Isometric contractions wererecorded as changes in grams of force on a Beckman Dynograph withStatham UC-3 transducers and microscale accessory attachments. Tissueswere allowed to equilibrate 1 to 2 hours before exposure to drugs.Cumulative agonist concentration-response curves were generated intissues and no tissue was used to generate more than two agonistconcentration-response curves. Results are expressed as a mean EC₅₀ andthe maximal response expressed as a percentage of the maximal tissuecontraction response to 67 mM KCl administered initially to each tissue.

This vasoconstriction assay measures two important parameters, saphenousvein contraction (EC₅₀) and maximal contraction as a % maximal KClresponse (%_(max) KCl). The saphenous vein contraction (EC₅₀) is ameasure of the dose required to contract tissue to 50% of the maximalresponse that the specific compound is capable of mediating. The maximalresponse that the saphenous vein is capable of exhibiting is measuredafter administration of a high concentration (67 mM) of KCl. The %maximal KCl contraction is the ratio of the maximal response that thespecific compound is capable of mediating divided by the maximalresponse that the tissue can produce upon stimulation with KCl. Forpurposes of this application, a compound may be considered to not havesignificant vasoconstrictive activity if it produces a maximalcontraction of less than or equal to 5% of the contraction produced bythe 67 mM KCl positive control at compound concentrations of up to 100μM.

Representative compounds of the present invention were tested with theabove saphenous vein assay and found to not be significantlyvasoconstrictive. This contrasts greatly with prior art compounds forthe treatment of migraine targeting the neural vasoconstrictive modelfor migraine treatment, which compounds were selected on the basis ofstrong vasoconstrictive activity, as for example, sumatriptan, which hasan EC₅₀ of 0.66 mM and a %_(max) KCl of 64.20 in this assay.

Specifidity Index

The specificity of compounds of the present invention for 5-HT_(1F)mediated inhibition of neuronal protein extravasation versusvasoconstrictive activity can be expressed with a Specificity Index,which is the ratio of vasoconstriction to efficacy in inhibitingneuronal protein extravasation:

${{Specificity}\mspace{14mu}{Index}} = \frac{{Corrected}\mspace{14mu}{Vasconstriction}\mspace{14mu}{EC}_{50}\mspace{14mu}(M)}{{Extravasation}\mspace{14mu}{ID}_{50}\mspace{14mu}\left( {{mMol}/{kg}} \right)}$

The Corrected Vasoconstriction takes into consideration the maximalcontraction relative to KCl for each individual compound, and is definedas the vasoconstriction EC₅₀ value divided by the %_(max) KCl.

For example, sumatriptan has a corrected vasoconstriction EC₅₀ of1.03×10⁻⁸ M (0.66 mM EC₅₀÷64.20%_(max) KCl) and an extravasationinhibition ID₅₀ of 2.6×10⁻⁸ mMol/Kg, giving a Specificity Index of 0.40.

Thus the procedure for determining the Specificity Index of any givencompound is as follows:

1. Measure the affinity of the compound for the 5-HT_(1F) receptor usingthe radioligand binding method described above;

2. Once affinity for the 5-HT_(1F) receptor is established, determinewhether the compound is an agonist, partial agonist or antagonist of the5-HT_(1F) receptor by its response in the above described cAMP assay;

3. If the compound is shown to be an agonist or partial agonist with anE_(max) of at least about 50%, measure efficacy of the compound ininhibition of protein extravasation and saphenous vein contraction usingthe above described assays; and

4. Calculate the Specificity Index as shown above.

While compounds with a Specificity Index greater than 1 are useful forthe methods and uses of the present invention, larger values for theSpecificity Index are preferred. A larger Specificity Index indicatesgreater specificity for efficacy in inhibition of neuronal proteinextravasation over vasoconstriction. Thus, preferred compounds have aSpecificity Index of greater than or equal to 10 (at least 10),preferably greater than or equal to 100 (at least 100). More preferredcompounds have a Specificity Index of greater than or equal to 1000 (atleast 1000), and yet more preferred compounds have Specificity Indexesgreater than or equal to 5000 (at least 5000).

Formulations

The type of formulation used for the administration of the compoundsemployed in the methods of the present invention may be dictated by theparticular compounds selected, the type of pharmacokinetic profiledesired from the route of administration, and the state of the patient.

Formulations amenable to oral, sublingual, nasal or injectableadministration are prepared in a manner well known in the pharmaceuticalart and comprise at least one active compound. See, e.g., REMINGTON'SPHARMACEUTICAL SCIENCES, (16th ed. 1980).

In general, a formulation of the present invention includes an activeingredient (a compound of formula I) and is usually mixed with anexcipient, diluted by an excipient or enclosed within such a carrierwhich can be in the form of a capsule, sachet, paper or other container.When the excipient serves as a diluent, it can be a solid, semi-solid,or liquid material, which acts as a vehicle, carrier or medium for theactive ingredient. Thus, the formulations can be in the form of tablets,pills, powders, lozenges, sachets, cachets, elixirs, suspensions,emulsions, solutions, syrups, aerosols (as a solid or in a liquidmedium), ointments containing for example up to 10% by weight of theactive compound, soft and hard gelatin capsules, gels, suppositories,sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g., about 40 mesh. In oneembodiment of the present invention, the particle size range is betweenabout 0.1 μm to about 100 μm.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompounds of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The following formulation examples are illustrative only and are notintended to limit the scope of the present invention. The term “activeingredient” refers to a compound of formula I.

Formulation Example 1 Hard Gelatin Capsules

Quantity Ingredient (mg/capsule)2,4,6-Trifluoro-N-[6-(1-methyl-piperidine- 30.04-carbonyl)-pyridin-2-yl]-benzamide hydrochloric acid salt Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

Formulation Example 2 Tablet

Quantity Ingredient (mg/tablet)2-Chloro-6-fluoro-N-[6-(1-methyl-piperidine- 25.04-carbonyl)-pyridin-2-yl]-benzamide mono-hydrochloric acid saltCellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearicacid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

Formulation Example 3 Dry Powder Inhaler

Ingredient Weight % 2,4,6-Trifluoro-N-methyl-N-[6-(piperidine- 54-carbonyl)-pyridin-2-yl]-benzamide Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Formulation Example 4 Tablet

Quantity Ingredient (mg/tablet) 2-Fluoro-N-[6-(1 -methyl-piperidine-30.0 4-carbonyl)-pyridin-2-yl]-isonicotinamide Starch 45.0Microcrystalline cellulose 35.0 Polyvinylpyrrolidone 4.0 (as 10%solution in water) Sodium carboxymethyl starch 4.5 Magnesium stearate0.5 Talc 1.0 Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C.-60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Formulation Example 5 Capsules

Quantity Ingredient (mg/capsule) Furan-3-carboxylic acid[6-(1-methyl-40.0 piperidine-4-carbonyl)-pyridin-2-yl]-amide Starch 109.0 Magnesiumstearate 1.0 Total 150.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

Formulation Example 6 Suspensions

Ingredient Amount 4-Fluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-2-trifluoromethyl-benzamide mono-hydrochloric acid salt50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%)Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate10.0 mg Flavor and color q.v. Purified water to 5.0 ml

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Formulation Example 7 Capsules

Quantity Ingredient (mg/capsule)4-Chloro-2-methoxy-N-[6-(1-methyl-piperidine- 15.04-carbonyl)-pyridin-2-yl]-benzamide Starch 407.0 Magnesium stearate 3.0Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 425 mg quantities.

Formulation Example 8 Intravenous Formulation

Ingredient Quantity 2-Ethoxy-N-[6-(1-methyl-piperidine- 250.0 mg4-carbonyl)-pyridin-2-yl]-benzamide Isotonic saline 1000 ml

Formulation Example 9 Sublingual or Buccal Tablets

Quantity Ingredient (mg/tablet)2,4,6-Trifluoro-N-[6-(1-methyl-piperidine- 10.04-carbonyl)-pyridin-2-yl]-benzamide hemi-succinnic acid salt Glycerol210.5 Water 143.0 Sodium citrate 4.5 Polyvinyl alcohol 26.5Polyvinylpyrrolidone 15.5 Total 410.0 mg

The glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous stirring andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the solution is cooled to about 50-55° C. and the activeingredient is slowly admixed. The homogenous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 2-4 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

Formulation Example 9 Sublingual or Buccal Tablets

Ingredient Quantity (mg/tablet)2,4,6-Trifluoro-N-[6-(1-methyl-piperidine- 5.0 (freebase equivalent)4-carbonyl)-pyridin-2-yl]-benzamide hemi-succinnic acid salt Mannitol 20Gelatine 2.0 Water add to total volume of 100 μL Total 27.0 mg

The compound was dissolved in water containing 20% mannitol and 2%gelatine to provide a stock solution at a concentration of 50 mg/mL(free base equivalent). The solution was aliquoted into forms holding100 μL solution each. The formulation was then frozen at −20° C. for 3hours and freeze dried.

Formulation Example 8 Intravenous Formulation

Quantity per Ingredient 1.0 mL Formulation2,4,6-Trifluoro-N-[6-(1-methyl-piperidine- 1.16 mg4-carbonyl)-pyridin-2-yl]-benzamide hemi-succinnic acid salt Mannitolparenteral 50.0 mg Water for injection: q.s. to 1.0 mL

The compound and mannitol are dissolved in water and then water is addedto obtain the desired final volume. The solution is then sterilefiltered and aseptically filled into suitable vials.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical formulationscomprising a pharmaceutically acceptable excipient and at least oneactive ingredient. These formulations can be administered by a varietyof routes including oral, buccal, rectal, intranasal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Many of thecompounds employed in the methods of this invention are effective asboth injectable and oral compositions.

In order to administer transdermally, a transdermal delivery device(“patch”) is needed. Such transdermal patches may be used to providecontinuous or discontinuous infusion of a compound of the presentinvention in controlled amounts. The construction and use of transdermalpatches for the delivery of pharmaceutical agents is well known in theart. See, e.g., U.S. Pat. No. 5,023,252. Such patches may be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, which is herein incorporated byreference. The delivery of hydrophilic drugs may be enhanced byintra-arterial infusion of hypertonic solutions which can transientlyopen the blood-brain barrier.

In one preferred embodiment of the present invention, there is provideda pharmaceutical formulation comprising at lest one active compound asdescribed above in a formulation adapted for buccal and/or sublingual,or nasal administration. This embodiment provides administration of theactive compound in a manner that avoids gastric complications, such asfirst pass metabolism by the gastric system and/or through the liver.This administration route may also reduce adsorption times, providingmore rapid onset of therapeutic benefit. The compounds of the presentinvention may provide particularly favorable solubility profiles tofacilitate sublingual/buccal formulations. Such formulations typicallyrequire relatively high concentrations of active ingredients to deliversufficient amounts of active ingredients to the limited surface area ofthe sublingual/buccal mucosa for the relatively short durations theformulation is in contact with the surface area, to allow the absorptionof the active ingredient. Thus, the very high activity of the compoundsof the present invention combined with their high solubilities,facilitate their suitability for sublingual/buccal formulation.

A compound of formula I is preferably formulated in a unit dosage form,each dosage containing from about 0.001 to about 100 mg, more usuallyabout 1.0 to about 30 mg, of the active ingredient. The term “unitdosage form” refers to physically discrete units suitable as unitarydosages for human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient as described above.

The compounds are generally effective over a wide dosage range. Forexamples, dosages per day normally fall within the range of about 0.0001to about 30 mg/kg of body weight. In the treatment of adult humans, therange of about 0.1 to about 15 mg/kg/day, in single or divided dose, isespecially preferred. However, it will be understood that the amount ofthe compound actually administered will be determined by a physician, inthe light of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compound orcompounds administered, the age, weight, and response of the individualpatient, and the severity of the patient's symptoms, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smallerdoses for administration throughout the day.

What is claimed is:
 1. A method for the treatment of migraine in amammal comprising administering to a mammal in need of such treatment aneffective amount of2,4,6-trifluoro-N-[6-[(1-methyl-4-piperidinyl)carbonyl]-2-pyridinyl]-benzamideor a pharmaceutically acceptable acid addition salt thereof.
 2. A methodfor the treatment of migraine in a mammal comprising administering to amammal in need of such treatment an effective amount of2,4,6-trifluoro-N-[6-[(1-methyl-4-piperidinyl)carbonyl]-2-pyridinyl]-benzamidehydrochloride salt.
 3. A method for the treatment of migraine in amammal comprising administering to a mammal in need of such treatment aneffective amount of2,4,6-trifluoro-N-[6-[(1-methyl-4-piperidinyl)carbonyl]-2-pyridinyl]-benzamidehydrochloride salt.